Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal

ABSTRACT

The present invention provides methods and compositions for the treatment of ion imbalances using core-shell composites and compositions comprising such core-shell composites. In particular, the invention provides core-shell particles and compositions comprising potassium binding polymers, and core-shell particles and compositions comprising sodium binding polymers, and in each case, pharmaceutical compositions thereof. Methods of use of the polymeric and pharmaceutical compositions for therapeutic and/or prophylactic benefits are also disclosed. The compositions and methods of the invention offer improved approaches for treatment of hyperkalemia and other indications related to potassium ion homeostasis, and for treatment of hypertension and other indicates related to sodium ion homeostasis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/053,725, filed Oct. 15, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/901,918, filed May 24, 2013, which is acontinuation of U.S. patent application Ser. No. 12/088,625, filed Sep.30, 2008, which is a U.S. PCT National of PCT/US2006/038602, filed Mar.30, 2005, which claims the benefit of U.S. Provisional Application Ser.No. 60/723,073 which was filed Sep. 30, 2005. The entire content ofthese applications is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Potassium (K⁺) is the most abundant intracellular cation, comprising˜35-40 mEq/kg in humans. See Agarwal, R, et al. (1994) Gastroenterology107: 548-571; Mandal, A K (1997) Med Clin North Am 81: 611-639. Only1.5-2.5% of this is extracellular. Potassium is obtained through thediet, mainly through vegetables, fruits, meats and dairy products, withcertain food such as potatoes, beans, bananas, beef and turkey beingespecially rich in this element. See Hunt, C D and Meacham, S L (2001) JAm Diet Assoc 101: 1058-1060; Hazell, T (1985) World Rev Nutr Diet 46:1-123. In the US, intake is ˜80 mEq/day. About 80% of this intake isabsorbed from the gastrointestinal tract and excreted in the urine, withthe balance excreted in sweat and feces. Thus, potassium homeostasis ismaintained predominantly through the regulation of renal excretion.Where renal excretion of K⁺ is impaired, elevated serum K⁺ levels willoccur. Hyperkalemia is a condition wherein serum potassium is greaterthan about 5.0 mEq/L.

While mild hyperkalemia, defined as serum potassium of about 5.0-6mEq/L, is not normally life threatening, moderate to severe hyperkalemia(with serum potassium greater than (about) 6.1 mEq/L) can have graveconsequences. Cardiac arrythmias and altered ECG waveforms arediagnostic of hyperkalemia. See Schwartz, M W (1987) Am J Nurs 87:1292-1299. When serum potassium levels increases above about 9 mEq/L,atrioventricular dissociation, ventricular tachycardia, or ventricularfibrillation can occur.

Hyperkalemia is rare in the general population of healthy individuals.However, certain groups definitely exhibit a higher incidence ofhyperkalemia. In patients who are hospitalized, the incidence ofhyperkalemia ranges from about 1-10%, depending on the definition ofhyperkalemia. Patients at the extremes of life, either premature orelderly, are at high risk. The presence of decreased renal function,genitourinary disease, cancer, severe diabetes, and polypharmacy canalso predispose patients to hyperkalemia.

Most of the current treatment options for hyperkalemia are limited touse in hospitals. For example, exchange resins, such as Kayexalate, arenot suitable for outpatient or chronic treatment, due to the large dosesnecessary that leads to very low patient compliance, severe GI sideeffects and significant introduction of sodium (potentially causinghypernatremia and related fluid retention and hypertension). Diureticsthat can remove sodium and potassium from patients via the kidneys areoften limited in their efficacy due to underlying kidney disease andfrequently related diuretic resistance. Diuretics are alsocontraindicated in patients where a drop in blood pressure and volumedepletion are undesired (e.g. CHF patients that in addition to sufferingfrom low blood pressure are often on a combination of drugs such as ACEinhibitors and potassium sparing diuretics such as spironolactone thatcan induce hyperkalemia).

The use of cation-binding resins for binding inorganic monovalentcations such as potassium ion and sodium ion has been reported. Forexample, U.S. Pat. No. 5,718,920 to Notenbomer discloses polymericcore-shell particles said to be effective for binding cations such assodium ion and potassium ion.

WO 05/097081 and WO 05/020752 describe core-shell particles for bindingtarget solutes. WO 05/020752 describes core-shell particles having shellcomponents comprising polymers, including in one embodiment polymersproduced by free radical polymerization of ethylenic monomers. Inanother embodiment, commercially available polymers, such as Eudragitpolymers, are described. Although WO 05/020752 describes core-shellparticles that represent an advance in core-shell technology and the usethereof, further improvement with respect to the selective binding andretention of monovalent cations over divalent cations remains desirable,especially as applied to core-shell particles advantaged for use intreating hyperkalemia. Similarly, WO 05/097081 describes potassiumbinding core-shell particles wherein the shell component comprisespolymers, including for example commercially available Eudragit polymer,or (in an alternative embodiment), benzylated polyehtyleneiminepolymers. Although WO 05/020752 likewise represents an advance incore-shell technology and the use thereof, further opportunity existsfor improvement with respect to permselectivity, especially as appliedto core-shell particles advantaged for use in treating hyperkalemia.

Notwithstanding the progress made in the art, there remains a need forimproved compositions for binding inorganic monovalent cations such aspotassium ion and sodium ion, and especially, for binding suchmonovalent cations selectively over divalent cations such as magnesiumion and calcium ion. In particular, there remains a need for improvedcore-shell particles having a therapeutically effective binding capacityin the physiologically relevant pH range for potassium ion or sodiumion, where such core-shell particles are substantially non-degradable,substantially non-absorbable and are suitable with respect to lack oftoxicity. Likewise, there remains a need in the art for improved methodsapplying such improved compositions, for example in pharmaceutical andother applications involving the removal of monovalent cations from anenvironment. In particular, there remains a significant need forimproved treatment of hyperkalemia, and related indications using suchimproved compositions.

SUMMARY OF THE INVENTION

Methods.

The present invention is directed, in a first general aspect, to methodsfor removal of monovalent cations, preferably inorganic monovalentcations such as potassium ions and sodium ions, from an environmentcomprising such cations, such as the gastrointestinal tract of a mammal.Preferably, the environment comprises one or more competing solutes, inparticular one or more competing divalent cations, preferably inorganicdivalent cations such as magnesium ion or calcium ion. The methods arepreferably applied for removing potassium ion from a gastrointestinaltract of a mammal.

In one first embodiment within this first aspect of the invention, themethod comprises administering a pharmaceutical composition (such as acore-shell particle) to the mammal, where the pharmaceutical compositioncomprises a permselective polymer for binding potassium ion overmagnesium ion (and preferably for binding both sodium ion and potassiumion over both magnesium ion and calcium ion). The permselectivity of thepharmaceutical composition persists during transit of the core-shellparticle through the small intestine and the colon. The pharmaceuticalcomposition preferentially exchanges and retains potassium ion oversodium ion in a lower colon of the gastrointestinal tract. Atherapeutically effective amount of potassium ion is from thegastrointestinal tract of the mammal. Preferably in this embodiment, thecore-shell particle can transit through the gastrointestinal tract ofthe mammal over a period of at least (about) 30 hours, or in some cases,over a longer period of at least (about) 36 hours, or 42 hours or 48hours.

In another second embodiment within this aspect of the invention, acore-shell particle is administered to mammal, preferably to a human.The core-shell particle comprises a core component and a shellcomponent, the core component being a polymer having a capacity forbinding potassium ion, and the shell component being a permselectivepolymer for binding potassium ion over magnesium ion (and preferably forbinding both sodium ion and potassium ion over both magnesium ion andcalcium ion). The permselectivity of the core-shell particle forpotassium ion over magnesium ion persists during transit of thecore-shell particle through the small intestine and the colon. Thecore-shell particle preferentially binds (e.g. exchanges) and retainspotassium ion over sodium ion in a lower colon of the gastrointestinaltract. A therapeutically effective amount of potassium ion is removedfrom the gastrointestinal tract of the mammal. Preferably in thisembodiment, the core-shell particle can transit through thegastrointestinal tract of the mammal over a period of at least (about)30 hours, or in some cases, over a longer period of at least (about) 36hours, or 42 hours or 48 hours.

In a further third embodiment of the first aspect of the invention, theinvention is directed to methods for treating a pharmaceuticalindication based on or derived directly or indirectly from abnormallyelevated monovalent cation, such as abnormally elevated serum potassiumion or abnormally elevated serum sodium ion. The method comprisesremoving potassium ion from a gastrointestinal tract of a mammalaccording to the first or second embodiments of this invention, as setforth above and as more specifically described hereinafter. The methodsand compositions of the invention are suitable for therapeutic and/orprophylactic use in such treatments. For example, the pharmaceuticalcompositions of the invention can be used to treat hyperkalemia usingpotassium-binding core-shell particles. In one embodiment, thecore-shell particles comporising potassium binding compositions are usedin combination with drugs that cause potassium retention, such aspotassium-sparing diuretics, angiotensin-converting enzyme inhibitors(ACEIs), Angiotensin receptor blockers (ARBs), non-steroidalanti-inflammatory drugs, heparin, or trimethoprim.

In a further fourth embodiment of this first general (methods) aspect ofthe invention, the invention is directed to the use of a compositioncomprising a core-shell particle for manufacture of a medicament. Themedicament is preferably for use for prophylactic or therapeutictreatment of various indications, as described herein. The compositioncan comprise core-shell particles, optionally in combination with one ormore pharmaceutically acceptable excipients. The medicament can be usedto remove potassium ion from a gastrointestinal tract of a mammalaccording to the first or second embodiments of this invention, as setforth above and as more specifically described hereinafter.

Compositions of Matter.

In another, second general aspect, the present invention providescompositions of matter, such as pharmaceutical compositions, forremoving potassium ion from a gastrointestinal tract of a mammal.

In a first embodiment within the second aspect of the invention, thepharmaceutical composition the pharmaceutical composition can comprise apolymer having a capacity for binding potassium ion, and thepharmaceutical composition can have a persistent selectivity forpotassium ion over magnesium ion. The pharmaceutical composition isfurther characterized by one or more of

(a) the pharmaceutical composition having a specific binding forpotassium ion of at least (about) 1.0 mmol/gm, preferably at least(about) 1.5 mmol/gm, preferably at least (about) 2.0 mmol/gm achievedwithin a potassium-binding period of less than (about) 24 hours,preferably less than (about) 18 hours, preferably less than (about) 12hours, preferably less than (about) six hours, and the pharmaceuticalcomposition having a specific binding for magnesium ion of not more than(about) 3.0, preferably not more than (about) 2.0, preferably not morethan (about) 1.0 mmol/gm maintained over a magnesium-binding period ofmore than (about) eighteen hours, preferably more than (about) 24 hours,

(b) the pharmaceutical composition having a relative binding forpotassium ion of at least (about) 20%, preferably at least (about) 30%,more preferably at least (about) 40%, in each case by mole of the totalbound cation, achieved within a potassium-binding period of less than(about) 24 hours, preferably less than (about) 18 hours, preferably lessthan (about) 12 hours, preferably less than (about) six hours, and thepharmaceutical composition having a relative binding for magnesium ionof not more than (about) 70%, preferably not more than (about) 60%,preferably not more than (about) 50%, preferably not more than (about)40%, in each case by mole of the total bound cation, maintained over amagnesium-binding period of more than (about) eighteen hours, preferablymore than (about) 24 hours, or

(c) the pharmaceutical composition having a time persistence forpotassium ion defined as the time needed to reach (about) 80% of theequilibrium binding, t₈₀, of not more than (about) 24 hours, preferablynot more than (about) 18 hours, preferably not more than (about) 12hours, preferably not more than (about) 6 hours, and the pharmaceuticalcomposition having a time persistence for magnesium ion defined as thetime needed to reach (about) 80% of the equilibrium binding, t₈₀, ofmore than (about) 18 hours, preferably more than (about) 24 hours.

In each case (a), (b) or (c), values are determined in vitro in an assayselected from the group consisting of

(i) a first assay consisting essentially of incubating thepharmaceutical composition at a concentration of 4 mg/ml in a solutionconsisting essentially of 55 mM KCl, 55 mM MgCl₂ and 50 mM2-morpholinoethanesulfonic acid, monohydrate, at a pH of 6.5 and atemperature of 37° C. for 48 hrs with agitation, and directly orindirectly measuring cations bound to the pharmaceutical compositionover time,

(ii) a second assay consisting essentially of incubating thepharmaceutical composition at a concentration of 4 mg/ml in a solutionconsisting essentially of 50 mM KCl, 50 mM MgCl₂, 50 mM2-morpholinoethanesulfonic acid, monohydrate, 5 mM sodium taurocholate,30 mM oleate and 1.5 mM citrate, at a pH of 6.5 and a temperature of 37°C. for 48 hrs with agitation, and directly or indirectly measuringcations bound to the pharmaceutical composition over time, and

(iii) a third assay consisting essentially of incubating thepharmaceutical composition at a concentration of 4 mg/ml in fecal watersolution, the fecal water solution being a filtered centrifugalsupernatant derived by centrifuging human feces for 16 hours at 50,000 gat 4° C. and then filtering the supernatant through a 0.2 um filter, thepharmaceutical composition being incubated in the fecal water solutionat a temperature of 37° C. for 48 hrs with agitation, and directly orindirectly measuring cations bound to the pharmaceutical compositionover time, and combinations of one or more of the first assay, thesecond assay and the third assay. In one approach within this firstembodiment of the second aspect of the invention, for each case (a) and(b), the potassium-binding period is preferably less than (about) 24hours and the magnesium-binding period is preferably more than (about)24 hours. In another approach within such embodiment, for each case (a)and (b), the potassium-binding period is preferably less than (about) 18hours and the magnesium-binding period is preferably more than (about)18 hours. In a further approach within such embodiment, for each case(a) and (b), the potassium-binding period is preferably less than(about) 12 hours and the magnesium-binding period is preferably morethan (about) 18 hours.

In an additional approach within such embodiment, for each case (a) and(b), the potassium-binding period is preferably less than (about) 6hours and the magnesium-binding period is preferably more than (about)18 hours. Similarly, in one approach within this first embodiment of thesecond aspect of the invention, for case (c), the potassium-bindingperiod is preferably not more than (about) 24 hours and themagnesium-binding period is preferably more than (about) 24 hours. Inanother approach within such embodiment, for case (c), thepotassium-binding period is preferably not more than (about) 18 hoursand the magnesium-binding period is preferably more than (about) 18hours. In a further approach within such embodiment, for case (c), thepotassium-binding period is preferably not than (about) 12 hours and themagnesium-binding period is preferably more than (about) 18 hours. In anadditional approach within such embodiment, for case (c), thepotassium-binding period is preferably not more than (about) 6 hours andthe magnesium-binding period is preferably more than (about) 18 hours.

A further third embodiment of the second general aspect of the presentinvention is directed to a core-shell particle comprising an inner corecomponent and a shell component. The inner core component comprises acation exchange polymer. The shell component encapsulates the corecomponent and comprises a net positively charged crosslinked aminepolymer containing amine moieties, at least 1% and preferably at least2% of the amine moieties being quaternary ammonium. Preferably in suchembodiment, the core-shell particle has a size of (about) 1 μm to(about) 500 μm and a binding capacity for potassium of at least (about)1.5 mmol/g at a pH greater than 5.5. Such core-shell particles are, inpreferred use aspects, administered to a mammal for passage through thegastrointestinal tract of the mammal.

A further fourth embodiment of the second general aspect of the presentinvention is directed to a core-shell particle comprising and inner corecomponent and a shell component. The inner core component comprises acation exchange polymer. The shell component encapsulates the corecomponent and comprises a net positively charged crosslinked aminepolymer, the polymer comprising amine moieties substituted by an(alk)heterocyclic moiety having the formula —(CH₂)_(m)—HET-(R_(x))_(t)or an (alk)aryl moiety having the formula —(CH₂)_(m)—Ar—(R_(x))_(t),wherein m is 0-10, t is 0-5, HET is a heterocyclic moiety, Ar is an arylmoiety, and R_(x) is hydrocarbyl or substituted hydrocarbyl, and—(CH₂)_(m)—Ar—(R_(x))_(t) is other than benzyl. Such core-shellparticles are, in preferred use aspects, administered to a mammal forpassage through the gastrointestinal tract of the mammal.

In a further fifth embodiment of the second general aspect of theinvention, the invention is directed to a composition for use as apharmaceutical. Preferably, the invention is directed to a compositionfor use in therapy (including for use in prophylactic or therapeutictherapy) for treatment of various indications, as described above belowwith respect to the first aspect (methods) of the invention. Thecomposition can comprise a pharmaceutical composition such as acore-shell particles, for example as described above in connection withthe first, second, third and fourth embodiments of this aspect of theinvention. The composition can optionally comprise one or morepharmaceutically acceptable excipients and additionally oralternatively, optionally can be applied in combination with a liquidmedia for suspending or dispersing the composition (e.g., core-shellparticles). The composition can be formulated into any suitable form(e.g., tablets, etc., as more fully described below). The core-shellparticle can be used as described above with respect to the one firstembodiment of the first aspect of the invention.

In the various embodiments of the first and second aspects of theinvention, the selectivity (e.g., permselectivity) of the pharmaceuticalcomposition (such as core-shell particles) of the invention issufficiently persistent to have a beneficial effect, such as abeneficial prophylactic or a beneficial therapeutic effect. Inparticular, in applications involving the gastrointestinal environment,the compositions (and core-shell particles) of the invention can removea greater amount of potassium ion than sodium ion from thegastrointestinal tract (within a potassium-binding period representativeof the transit time for the lower colon), and can have a persistentselectivity for potassium ion over one or more divalent ions, e.g.,magnesium ion, calcium ion (over a divalent ion-binding periodrepresentative of the transit time through the gastrointestinal tract ora relevant portion there of (e.g., through the small intestine and thecolon)).

In any embodiment of the first general aspect or of the second generalaspect of the present invention, the core shell particle can be furthercharacterized as being or as having one or more additional features,described as follows in the paragraphs included hereinafter within theSummary of the Invention and as detailed in the Detailed Description ofthe Invention. Such additional features are considered to be part of theinvention in any and all possible combinations with each other and withone or more embodiments of the invention as mentioned in connection withthe first or second aspect thereof.

Shell Component.

In particularly preferred embodiments, the shell component comprises acrosslinked polyvinylic (e.g., polyvinylamine) polymer having one ormore further features or characteristics (alone or in variouscombinations), as described herein. In some embodiments, the polyvinylicpolymer can be a densely crosslinked polyvinylic polymer. In someembodiments, for example, the polyvinylic polymer can be a product of acrosslinking reaction comprising crosslinking agent and polyvinylicpolymer (e.g., of repeat units of the polymer or of crosslinkablefunctional groups of the polymer) in a ratio of not less than (about)2:1, and preferably in a ratio ranging from (about) 2:1 to (about) 10:1,ranging from (about) 2.5:1 to (about) 6:1, or ranging from (about) 3:1to (about) 5:1 and in some embodiments in a ratio of (about) 4:1, ineach case on a molar basis. In some embodiments, the crosslinked shellpolymer can be a crosslinked polyvinylamine polymer comprising acrosslinking moieties and amine moieties in a ratio of not less than(about) 0.05:1, preferably not less than (about) 0.1:1, and preferablyin a ratio ranging from (about) 0.1:1 to (about) 1.5:1, more preferablyranging from (about) 0.5:1 to (about) 1.25:1, or from (about) 0.75:1 to(about) 1:1, in each case based on mole equivalent of crosslinkingmoiety to amine moiety in the crosslinked polyvinylamine polymer.

Shell Crosslinking Agents.

The shell can be crosslinked with a crosslinking agent. Generally, thecrosslinking agent comprises a compound having at least two aminereactive moieties. In some embodiments, the crosslinking agent for theshell component can be a hydrophobic crosslinking agent.

Robustness.

The core-shell particle of any aspect or embodiment of the invention ispreferably sufficiently robust to survive in the environment of use—forexample, to pass through the gastrointestinal system (or an in-vitroassay representative thereof) for pharmaceutical applications—withoutsubstantially disintegrating such core shell particle, and/or preferablywithout substantially degrading physical characteristics and/orperformance characteristics of the core-shell particle. In preferredembodiments, the shell component of the core-shell composition isessentially not disintegrated and/or has physical characteristics and/orperformance characteristics that are essentially not degraded underphysiological conditions of the gastrointestinal tract (or in vitrorepresentations or mimics thereof) during a period of time for residencein and passage through the environment of interest, such as thegastrointestinal tract.

Deformable Polymer.

In some embodiments, the shell component is preferably a deformablepolymer, and more preferably deformable crosslinked polymer that canaccommodate changes in the core component dimensions (e.g., due toswelling—such as from hydration in an aqueous environment; or e.g., doto manufacturing protocols—such as drying; or e.g., due to storage—suchas in a humid environment).

Non-Absorbed.

Preferably core-shell particles and the compositions comprising suchcore-shell particles are not absorbed from the gastro-intestinal tract.Preferably, (about) 90% or more of the polymer is not absorbed, morepreferably (about) 95% or more is not absorbed, even more preferably(about) 97% or more is not absorbed, and most preferably (about) 98% ormore of the polymer is not absorbed.

Potassium Binding Capacity.

The core-shell particle of any aspect or embodiment of the invention canhave an effective amount of a potassium binding core, such as apotassium binding polymer (e.g., a polymer having a capacity for bindingpotassium). In some embodiments, the core-shell particle can have atherapeutically effective amount of a potassium binding core, such thatupon being administered to a mammal subject, such as a human, thecore-shell particle effectively binds and removes an average of at least(about) 1.5 mmol (or 1.5 mEq) or higher of potassium per gm ofcore-shell particle. The core-shell particle can also be characterizedby its binding capacity based on in vitro binding capacity forpotassium, as described hereinafter in the Detailed Description of theInvention.

Selectivity.

Advantageously, core-shell particles of the invention are selective tomonovalent cations over divalent cations. The crosslinked shell polymercan be a permselective polymer, having a permselectivity for inorganicmonovalent cations over inorganic divalent cations. In preferredembodiments, the relative permeability of the shell polymer formonvalent ion versus divalent ion can be characterized by a permeabilityratio of permeability for monovalent ions (e.g., potassium ions) topermeability for divalent cations (e.g., Mg⁺⁺ and Ca⁺⁺), as measure insuitable environment-representative in vitro assays. For example, asmeasured in gastrointestinal representative assays, the permeabilityratio can be at least (about) at least (about) 2:1, and preferably atleast (about) 5:1, or at least (about) 10:1 or at least (about) 100:1,or at least (about) 1,000:1 or at least (about) 10,000:1. As measured ingastrointestinal representative assays, the permeability ratio canrange, for example, from (about) 1:0.5 to (about) 1:0.0001 (i.e., from(about) 2:1 to (about) 10,000:1), and can preferably range from (about)1:0.2 and (about) 1:0.01 (i.e., from (about) 5:1 to (about) 100:1).

Shell Amount/Thickness/Particle Size.

The core-shell particle can preferably comprise a shell component and acore component in a relative amount generally ranging from (about)1:1000 to (about) 1:2 by weight. In preferred embodiments, the relativeamount of shell component to core component can range from (about) 1:500to (about) 1:4 by weight, or ranging from (about) 1:100 to (about) 1:5by weight, or ranging from (about) 1:50 to (about) 1:10 by weight. Insome embodiments, shell component can have a thickness ranging from(about) 0.002 micron to (about) 50 micron, preferably (about) 0.005micron to (about) 20 microns, or from (about) 0.01 microns to (about) 10microns.

Product-by-Process.

The core-shell particles and compositions of the invention can be aproduct resulting from a process comprising steps for preparing acore-shell composite (such as a core-shell particle) comprising a corecomponent and a crosslinked shell polymer formed over a surface of thecore component. In particular, the core-shell particles and compositionsof the invention can be a product resulting from a certain multiphaseprocess with in situ crosslinking. A preferred process can comprise, inone general embodiment, forming a core-shell intermediate comprising acore component, and a shell polymer associated with a surface of thecore component. The core-shell intermediate is formed for example in afirst liquid phase. The core-shell intermediate is phase-isolated from abulk portion of the first liquid phase. Preferably, the core-shellintermediate is phase-isolated using a second liquid phase, the secondliquid phase being substantially immiscible with the first liquid phase.The phase-isolated core-shell intermediate is contacted with acrosslinking agent under crosslinking conditions (to crosslink the shellpolymer associated with the surface of the core component). Theresulting product is the core-shell composite comprising a cross-linkedshell polymer over a surface of a core component. Additional embodimentsof such process are described in further detail below, and productsresulting from such embodiments are likewise within the invention.

Polymeric Components.

In embodiments where the core component comprises a polymer, the polymercan be a homopolymer or a copolymer (e.g., binary, tertiary orhigher-order polymer), and can optionally be crosslinked. Copolymers ofthe core component can be random copolymers, block copolymers, orcopolymers having a controlled architecture prepared by living freeradical polymerization. The crosslinked polyvinylic polymer of the shellcomponent can likewise be a homopolymer or a copolymer (e.g., binary,tertiary or higher-order polymer). Copolymers of the shell component canbe random copolymers, block copolymers, or copolymers having acontrolled architecture prepared by living free radical polymerization.

Core Component.

In some embodiments, the core can be a commercially available cationexchange resin, such as polystyrenesulfonate (e.g., availablecommercially as a Dowex resin (Aldrich)), or such as polyacrylic acid(e.g., available commercially as Amberlite (Rohm and Haas)). In someembodiments, the core component can comprise a polymer selected from apoly-fluoroacrylic acid polymer, a poly-difluoromaleic acid polymer,polysulfonic acid, and combinations thereof, in each case optionally(and generally preferably) crosslinked. In some preferred embodimentsthe core-component polymer comprises 2-fluoroacrylic acid crosslinkedwith a crosslinking agent. The crosslinking agent for a polymeric corecomponent can be selected from the group consisting of divinylbenzene,1,7-octadiene, 1,6-heptadiene, 1,8-nonadiene, 1,9-decadiene,1,4-divinyloxybutane, 1,6-hexamethylenebisacrylamide, ethylenebisacrylamide, N,N′-bis(vinylsulfonylacetyl) ethylene diamine,1,3-bis(vinylsulfonyl) 2-propanol, vinylsulfone,N,N-methylenebisacrylamide polyvinyl ether, polyallylether, andcombinations thereof. In some preferred embodiments the crosslinkingagent are selected from divinylbenzene, 1,7-octadiene,1,4-divinyloxybutane, and combinations thereof. In some embodiments, thecore can be in its proton form, sodium form, potassium form, calciumform, ammonium form, or combinations thereof.

Advantageously, the compositions and methods of the invention providesubstantial advantages for removing monovalent ions from an environment,such as from a gastrointestinal tract of a mammal. In particular, thecompositions and methods of the invention provide improved selectivityfor binding monovalent ions preferentially over competing solutes,particularly over divalent cations such as magnesium ion and/or calciumion present in the environment. The compositions and methods of theinvention also provide improved retention of monovalent ions, even inthe presence of substantial concentrations of competing solutes such asdivalent cations, and even over long periods of time. The improvementsin performance characteristics realized by the compositions and methodsof the invention translate to substantial benefits for treatment of ionbalance disorders in humans and other mammals. In particular, forexample, the compositions and methods of the invention offer improvedapproaches (compositions and methods) for (prophylactic or therapeutic)treatment of hyperkalemia and other indications related to potassium ionhomeostasis, and for treatment of hypertension and other indicatesrelated to sodium ion homeostasis. Notably, such prophylactic and/ortherapeutic benefits can be realized using the compositions and methodsof the invention, while also reducing the risk of potential off-targeteffects (e.g., the risk of hypocalcemia and hypomagnesemia).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 through FIG. 12 are each graphs showing the binding profiles ofcore-shell particles of the invention for certain cations—shown as theamount of cation bound per unit weight of core-shell particle (meq/gm)over time. Data is shown for three core-shell particles comprising acrosslinked polyvinylamine shell over a polystyrenesulfonate core[xPVAm/Dowex(Na)] (prepared as in Examples 1 through 3) and for acontrol particle comprising polystyrene sulfonate—without a shell[Dowex(Na)], in each case as determined by three different in vitroassays representative of the gastrointestinal tract—as detailed inExample 4A (FIGS. 1 through 4), Example 4B (FIGS. 5 through 8), andExample 4C (FIGS. 9 through 12).

FIGS. 13A and 13B show SEM images of the core-shell particle[xPVAm/Dowex (Na)] prepared in Example 1 (Ref #253) at relatively lowmagnification (FIG. 13A) and at relatively high magnification (FIG.13B).

FIGS. 14A and 14B show SEM images of the core-shell particle[xPVAm/Dowex (Na)] prepared in Example 2 (Ref #293) at relatively lowmagnification (FIG. 14A) and at relatively high magnification (FIG.14B).

FIGS. 15A and 15B show SEM images of the core-shell particle[xPVAm/Dowex (Na)] prepared in Example 3 (Ref #291) at relatively lowmagnification (FIG. 15A) and at relatively high magnification (FIG.15B).

FIGS. 16A and 16B show SEM images of the a [Dowex (Na)] particle—withouta shell component (used as a control in the experiment of Example 4) atrelatively low magnification (FIG. 16A) and at relatively highmagnification (FIG. 16B).

FIGS. 17A through 17C show confocal images of the core particlealone—without shell [Dowex(Na)] (FIG. 17A), of the core-shell particle[xPVAm/Dowex (Na)] prepared in Example 2 (Ref #293) (FIG. 17B), and ofthe core-shell particle [xPVAm/Dowex (Na)] prepared in Example 1 (Ref#253) (FIG. 17C).

FIG. 18(a) is a graph showing binding profiles for beads having aDowex(Na) core with a crosslinked polyvinylamine (PVAm) shell (500 gramcoating batch) at 37° C. using Assay No. I (non-interfering (NI)conditions) where the bead concentration was 10 mg/ml.

FIG. 18(b) is a graph showing binding profiles for beads having aDowex(Na) core with a crosslinked polyvinylamine (PVAm) shell (500 gramcoating batch) at 37° C. using Assay No. II (potassium specificinterfering assay (K-SPIF) conditions) where the bead concentration was10 mg/ml.

FIG. 19 is a graph showing the binding profile in fecal extract of ADowex 50W X4-200 core without a shell and various test materialcontaining the same core, but with various crosslinked polyvinylamineshells.

FIG. 20 is a schematic of the study design for testing the effect ofcrosslinked polyvinylamine shells on cation excretion in swine.

FIG. 21(a) is a graph showing the excretion of sodium, potassium,magnesium, and calcium ions in feces of swine.

FIG. 21(b) is a graph showing the excretion of sodium, potassium,magnesium, and calcium ions in urine of swine.

FIG. 22 is a schematic of the study design for testing the effect ofcrosslinked polyvinylamine shells on cation excretion in rats.

FIG. 23(a) is a graph showing the excretion of sodium and potassium ionsin urine of rats.

FIG. 23(b) is a graph showing the excretion of sodium and potassium ionsin feces of rats.

FIG. 24(a) is a graph showing the effect of the ECH/Ben(50)-PEI ratio oncation binding of a core-shell particle containing a Dowex(Na) core witha crosslinked Ben(50)-PEI shell with an aqueous shell solution of pH 6.5during coating.

FIG. 24(b) is a graph showing the effect of the ECH/Ben(50)-PEI ratio oncation binding of a core-shell particle containing a Dowex(Na) core witha crosslinked Ben(50)-PEI shell with an aqueous shell solution of pH 7during coating.

FIG. 24(c) is a graph showing the effect of the ECH/Ben(50)-PEI ratio oncation binding of a core-shell particle containing a Dowex(Na) core witha crosslinked Ben(50)-PEI shell with an aqueous shell solution of pH 7.4during coating

FIG. 24(d) is a graph showing the effect of the ECH/Ben(35)-PEI ratio oncation binding of a core-shell particle containing a Dowex(Na) core witha crosslinked Ben(35)-PEI shell with an aqueous shell solution of pH 7.6during coating.

FIG. 25(a) is a graph showing the effect of the ECH/Ben(50)-PEI ratio oncation binding of a core-shell particle containing a Dowex(Na) core witha crosslinked Ben(50)-PEI shell where 20 wt. % of shell polymer was usedduring coating.

FIG. 25(b) is a graph showing the effect of the ECH/Ben(50)-PEI ratio oncation binding of a core-shell particle containing a Dowex(Na) core witha crosslinked Ben(50)-PEI shell where 15 wt. % of shell polymer was usedduring coating.

FIG. 25(c) is a graph showing the effect of the ECH/Ben(50)-PEI ratio oncation binding of a core-shell particle containing a Dowex(Na) core witha crosslinked Ben(50)-PEI shell where 10 wt. % of shell polymer was usedduring coating.

FIGS. 26(a) and 26(b) are graphs showing the magnesium ion bindingprofile of Ben(84)-PEI shells on Dowex(K) cores prepared by solventcoacervation. FIG. 25(b) further shows the stability of a Ben(84)-PEIshell on a Dowex(K) core after contact with an acidic aqueous solution.

FIG. 27(a) is a graph showing the magnesium ion binding profile ofcore-shell particles having a Ben(20)-PEI shell, a Ben(40)-PEI shell, orno shell on a Dowex(K) core.

FIG. 27(b) is a graph showing the magnesium ion binding profile ofcore-shell particles having a Ben(40)-PEI shell and a Dowex(K) corewhere the particles were prepared on a 0.5 gram or a 10 gram scale.

FIG. 28(a), 28(b), 28(c) are graphs showing the potassium ion andmagnesium ion binding profiles where the shell thickness is varied.Shell thicknesses approximated by the ratio of shell material to corematerial (expressed as wt. %) are 10 wt. % Ben(84)-PEI, 2 wt. %Ben(84)-PEI, and 7.6 wt. % Ben(65)-PEI, respectively.

FIG. 29 is a graph showing the potassium ion and magnesium ion bindingprofiles for two samples having a Dowex core and Ben-PEI shells ofdiffering quaternization degrees. The EC-24159-2 sample has a lowerquaternization degree than the EC-24159-8.

FIG. 30 is a graph showing the potassium ion, magnesium ion, and sodiumion binding profiles for samples having a Dowex core and Ben-PEI shellshaving different degrees of permanent quaternization.

FIG. 31 is a graph showing the relative intensities and the energy (ineV) of the electrons occupying the nitrogen is orbital for nitrogenatoms attached to different numbers of organic groups.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions of matter, includingpharmaceutical compositions and compositions for use as a pharmaceuticalor for use in therapy, in each case, said composition comprising acore-shell particle. The present invention also provides methods,including methods for removing monovalent cation, such as inorganicmonovalent cation, from an environment comprising such cation, and insome embodiments, removing such cation from a gastrointestinal tract ofa mammal. The invention also provides methods for treating apharmaceutical indication based on or derived directly or indirectlyfrom abnormally elevated monovalent cation, such as abnormally elevatedserum potassium ion (e.g., hyperkalemia) or abnormally elevated serumsodium ion (e.g., hypertension). The invention also provides for the useof a composition comprising a core-shell particle for manufacture of amedicament. The medicament is preferably for use for prophylactic ortherapeutic treatment of various indications, as described herein (inthis paragraph, in earlier paragraphs above, and in later paragraphsfollowing). The invention also provides kits for the treatment of animalsubjects, and preferably mammals.

The compositions and methods of the invention offer improvements overprior art approaches, in particular with respect to binding capacityfor, selectivity for and retention of monovalent ions. The compositionsand methods of the invention also provide substantial benefits fortreatment of ion balance disorders in humans and other mammals.

Core-Shell Particle

In general, the various aspects of the invention comprise a core-shellparticle. The core-shell particle comprises a core component and shellcomponent.

Because the core component has a net negative charge under physiologicalconditions (to provide the capacity for binding monovalent cation) andthe shell polymer has a net positive charge under physiologicalconditions, the core and shell components are significantly attracted toeach other and, as a result, there is a potential for the shell polymerand core component to form an interpenetrating polymer network.Interpenetration of the two components, however, will tend to reduce thecapacity of the core component for potassium. Interpenetration of thetwo components may also reduce the integrity of the shell layer andthereby reduce the permselectivity of the core-shell particles formonovalent cations over divalent cations. Thus, it is generallypreferred that the interpenetration of the material used for the shelland core components be minimized.

One factor affecting whether the core and shell components, especiallypolyelectrolyte polymers interpenetrate is the size of the shellpolyelectrolyte relative to the pore size of the core. In general, thepotential for interpenetration increases as the molecular weight of theshell polymer decreases or the pore size of the core increases. In someembodiments, therefore, the shell polymer molecular weight is greaterthan (about) 1500 daltons, preferably, greater than (about) 5000daltons, and still more preferably, greater than (about) 10,000 daltons.Similarly, in some embodiments, the average pore size of the cationexchange polymer core is less than (about) 1 μm; preferably, less than(about) 500 nm, still more preferably, less than (about) 250 nm; andeven more preferably, less than (about) 50 nm. In some embodiments, thecore-shell particle comprises a shell component comprising or consistingessentially of a shell polymer having a molecular weight greater than(about) 1500 daltons, preferably, greater than (about) 5000 daltons, andstill more preferably, greater than (about) 10,000 daltons, in each casecrosslinked with a suitable crosslinker, and a core component comprisingor consisting essentially of a cation exchange resin which is acrosslinked polymer having an average pore size of less than (about) 1μm; preferably, less than (about) 500 nm, still more preferably, lessthan (about) 250 nm; and even more preferably, less than (about) 50 nm,including each permutation of combinations of the foregoing molecularweights and average pore sizes. The embodiments described in thisparagraph are general features of the invention, and can be used incombination with each other feature of the invention, as describedherein.

The core component can generally comprise an organic material (e.g., anorganic polymer) or an inorganic material. Preferably, the corecomponent can comprise a capacity (e.g., the core component can comprisea polymer having a capacity) for binding monovalent cation (e.g., aninorganic monovalent cation such a potassium ion or sodium ion). Inpreferred embodiments, the core component will be a cation exchangeresin (sometimes referred to as a cation exchange polymer), preferablycomprising a crosslinked polymer. Suitable organic and inorganic corematerials are described below.

In general, the shell component comprises a crosslinked polymer, such asa crosslinked hydrophilic polymer. Preferably, the shell componentcomprises a crosslinked polymer having a vinylic repeat unit, such as avinylamine repeat unit or other amine-containing monomer derived repeatunit. The shell polymer can also comprise hydrophobic moieties, such asa copolymer (e.g., a random copolymer or block copolymer) having bothhydrophilic and hydrophobic repeat units. The shell component cancomprise a cationic polyelectrolyte, the polyelectrolyte comprising apolymer having a vinylamine repeat unit. In particularly preferredembodiments of the various aspects of the invention, the shell componentcomprises crosslinked polyvinylamine.

Shell Component

The shell component comprises a crosslinked shell polymer. Generally,the sequence of polymerization of a shell polymer, crosslinking of ashell polymer and/or coating of a shell polymer onto a core component isnot narrowly critical. In one embodiment, the shell polymer iscrosslinked during the polymerization reaction to form the crosslinkedpolymer; in an alternative embodiment, the monomer(s) is(are)polymerized and the resulting (uncrosslinked) polymer is subsequentlytreated with a crosslinking agent to form the crosslinked polymer. Inconnection with the former of the immediately-aforementioned embodimentsof this paragraph, the crosslinked polymer can be prepared before theshell polymer is coated onto the core; or alternatively, the crosslinkedpolymer can be coated onto the core, in situ, during the polymerizationreaction. In connection with the latter of the aforementionedembodiments of this paragraph, the shell polymer can be treated withcrosslinking agent to form a crosslinked polymer before the shellpolymer is coated onto the core, or alternatively, the (uncrosslinked)shell polymer can be coated onto the core before the shell polymer istreated with the crosslinking agent to form the crosslinked polymer).The following description applies with respect to each possible sequenceof polymerization, crosslinking and/or coating as described in thisparagraph, and explained in further detail below. The shell polymer cancomprise a hydrophilic polymer. The shell polymer can have an aminefunctional group. The shell polymer can comprise a polyvinylic polymer.The shell polymer can comprise a polyvinylamine polymer. Alternatively,the shell polymer may comprise a polyalkyleneimine polymer (e.g.,polyethyleneimine) polymer. Although polyvinylic polymers such aspolyvinylamine polymers and polyalkyleneimine polymers are preferredshell polymers, other shell polymers can be used in some embodiments ofthe invention. Some other shell polymers are described below, withoutbeing limiting to the invention.

The polymer (e.g., hydrophilic polymer or polyvinylic polymer, such aspolyvinylamine polymer or polyalkyleneimine polymer such aspolyethyleneimine) of the shell component can generally be a homopolymeror a copolymer (e.g., binary, tertiary or higher-order polymer).Copolymers of the shell component can be random copolymers, blockcopolymers, or controlled-architecture copolymers (e.g., copolymershaving a controlled architecture prepared by living free radicalpolymerization).

In one embodiment, the shell is a polymer containing repeat unitsderived from a vinyl monomer, and preferably from a monomer containing avinylamine group. In another embodiment, the shell is a polymercontaining repeat units derived from an alkyleneimine monomer. Ingeneral, permselectivity of the core-shell particle for monovalentcation over divalent cation can be influenced, at least in part, by theelectronic character of the shell component which, in turn, can beinfluenced by the relative number of repeat units in the shell componentderived from vinylamine, alkyleneimine or other amine-containingmonomers. Under physiological conditions, the amine moieties of suchrepeat units can be protonated, providing a source of a net positivecharge; by increasing the number density of amine derived repeat unitsrelative to other monomer derived repeat units, therefore, the cationiccharge density of the shell polymer can be increased under physiologicalconditions. Thus, in one embodiment it is preferred that the shellcomponent comprise a polymer having at least 10% of the repeat units ofthe polymer derived from amine containing monomers. In this embodiment,it is even more preferred that the shell component comprise a polymerhaving at least 20% of the repeat units of the polymer derived fromamine containing monomers. In this embodiment, it is even more preferredthat the shell component comprise a polymer and that at least 30% of therepeat units of the polymer be derived from amine containing monomers.Still more preferably in this embodiment, at least 50% of the repeatunits of the polymer be derived from amine containing monomers. Stillmore preferably in this embodiment, at least 75% of the repeat units ofthe polymer be derived from amine containing monomers. In someapproaches in this embodiment, it is preferable that least 100% of therepeat units of the polymer are derived from amine containing monomers.In each of the aforementioned, preferred amine-containing monomers arevinylamine monomer and/or alyleneimine monomers. In copolymer systems,vinylamine monomer derived repeat units, alkyleneimine monomer derivedrepeat units, or other amine-containing monomer derived repeat unitscan, each independently or in various combination, be included within acopolymer comprising other non-amine-containing monomer derived repeatunits, such as other non-amine-containing viniylic monomer derivedrepeat units. Such non-amine-containing vinylic monomer from which sucha copolymer can be derived include, for example, vinylamide monomers.Hence, in one embodiment of the invention, the shell polymer cancomprise a copolymer comprising a repeat unit derived from anamine-containing monomer and a repeat unit derived from anamide-containing monomer; particularly for example, a copolymercomprising repeat units derived from vinylamine and vinylamide monomersStill more preferably in this embodiment, the polymer is a homopolymerderived from a vinylamine containing monomer, a homopolymer derived froman alkyleneimine (e.g., ethyleneimine) monomer, or a copolymer derivedfrom a vinylamine containing monomer and an alkyleneimine (e.g.,ethyleneimine) monomer. In each embodiment described in this paragraph,it is preferred that the polymer be crosslinked.

The amine moiety of vinyl amine monomer derived units of a polymercontained by the shell component may be in the form of a primary,secondary, tertiary, or quaternary amine. Similarly, the amine moiety ofalkyleneimine monomer derived units of a polymer contained by the shellcomponent may be in the form of a secondary or tertiary amine, orquaternary ammonium. In some embodiments, at least a portion of theamine moieties are quaternary ammonium moieties, as describedhereinafter. The extent of substitution of the amine moiety, as well asthe hydrophilic/hydrophobic character of any such substituents can alsoinfluence the permselectivity of the shell component under physiologicalconditions. For example, in one embodiment, it is preferred that theshell component contain a polymer having vinylamine monomer derivedrepeat units, alkyleneimine monomer derived repeat units, or otheramine-containing monomer derived repeat units and that more than 10% ofthe amine moieties of such repeat units contain a hydrocarbyl,substituted hydrocarbyl, or heterocyclic substituent, preferably in eachcase, such substituent being a hydrophobic moiety. In some of theseembodiments, vinylamine monomer derived repeat units, alkyleneiminemonomer derived repeat units, or other amine-containing monomer derivedrepeat units can, each independently or in various combination, beincluded within a copolymer comprising other non-amine-containingmonomer derived repeat units, such as other non-amine-containingviniylic monomer derived repeat units. Such non-amine-containingviniylic monomer from which such a copolymer can be derived includes,for example, vinylamide monomers. Hence, in one embodiment of theinvention, the shell polymer can comprise a copolymer comprising arepeat unit derived from an amine-containing monomer and a repeat unitderived from an amide-containing monomer; particularly for example, acopolymer comprising repeat units derived from vinylamine and vinylamidemonomers. In general, the relative percentage of amine moietiescontaining a hydrocarbyl, substituted hydrocarbyl, or heterocyclicsubstituent (e.g., in each case, as a a hydrophobic moiety) can beinversely related to the amount of amine-containing repeat units in theshell component; thus, for example, when the percentage of repeat unitsderived from amine-containing monomer is relatively low, the percentageof amine-containing monomer derived units containing hydrocarbyl,substituted hydrocarbyl or heterocyclic substitutents (as compared tothe total number of amine-containing monomer derived repeat units) tendsto be greater. Thus, for example, in certain embodiments, it ispreferred that more than 25% of the amine-containing monomer derivedrepeat units contain a hydrocarbyl, substituted hydrocarbyl, orheterocyclic substituent. In certain embodiments, it is preferred thatmore than 50% of the amine-containing monomer derived repeat unitscontain a hydrocarbyl, substituted hydrocarbyl, or heterocyclicsubstituent. In certain embodiments, it is preferred that more than 98%or more than 99% or (about) 100% of the amine-containing monomer derivedrepeat units contain a hydrocarbyl, substituted hydrocarbyl, orheterocyclic substituent. The percentage of amine-containing monomerderived repeat units containing hydrocarbyl, substituted hydrocarbyl orheterocyclic substitutents, therefore, will typically be between 10 and(about) 100%, alternatively ranging from 25-75%, and for some approachesranging from 30-60% of the amine-containing monomer derived repeat unitsin the shell component. In each such embodiment described in thisparagraph, it is preferred that the polymer be crosslinked.

Preferably, the shell polymer can be a polyvinylamine polymer modifiedor derivitized to comprise one more alkyl moieties and/or one moreN-alkyl-aryl moieties.

A polyvinylamine shell polymer can, in one embodiment, be characterizedas a polymer or preferably a crosslinked polymer, in each case where thepolymer is represented by Formula I:

or a copolymer thereof, wherein n is at least 4, R₁ and R₂ areindependently selected from hydrogen, alkyl, phenyl, aryl, orheterocyclic, and A is a linker wherein A is nothing (i.e., represents acovalent bond between the N atom and the C atom of the polymer backbone)or is selected from alkyl, aryl, heterocyclic, carboxyalkyl(—CO₂-alkyl), carboxamidoalkyl (—CON-alkyl), or aminoalkyl. In oneembodiment, R₁ and R₂ are independently selected from hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclic moieties, and theresidue of crosslinking agents (described elsewhere herein to crosslinkthe polymer) or together, in combination with the nitrogen atom to whichthey are bonded, form a heterocylic (i.e., a vinylheterocyclic). Forexample, in this embodiment R₁ and R₂ may be independently selected fromhydrogen, optionally substituted alkyl, alkenyl, alkynyl,(alk)heterocyclic or (alk)aryl wherein (alk)heterocylic has the formula—(CH₂)_(m)—HET-(R_(x))_(t), (alk)aryl has the formula—(CH₂)_(m)—Ar—(R_(x))_(t), m is 0-10, t is 0-5, HET is a heterocyclicmoiety, Ar is an aryl moiety, and R_(x) is hydrocarbyl or substitutedhydrocarbyl. When R₁ or R₂ is —(CH₂)_(m)—HET-(R_(x))_(t) and theheterocyclic moiety, HET, is heteroaromatic or, when R₁ or R₂ is—(CH₂)_(m)—Ar—(R_(x))_(t), it is sometimes preferred that m be atleast 1. In addition, when R₁ or R₂ is —(CH₂)_(m)—Ar—(R_(x))_(t) and mis 1, it is sometimes preferred that t be at least 1. Further, when oneof R₁ and R₂ is —(CH₂)_(m)—Ar—(R_(x))_(t) or —(CH₂)_(m)—HET-(R_(x))_(t),it is sometimes preferred that the other be hydrogen, lower alkyl (e.g.,methyl, ethyl or propyl) or the residue of a crosslinking agent. In oneembodiment, R₁ is optionally substituted alkyl and R₂ is—(CH₂)_(m)—HET-(R_(x))_(t) or —(CH₂)_(m)—Ar—(R_(x))_(t), wherein m is0-10, t is 0-5, HET is a heterocyclic moiety, Ar is an aryl moiety, andR_(x) is hydrocarbyl or substituted hydrocarbyl. In another embodiment,R₁ and R₂ may be hydrogen, optionally substituted alkyl,—(CH₂)_(m)—HET-(R_(x))_(t) or —(CH₂)_(m)—Ar—(R_(x))_(t), and A ishydrocarbylene (e.g., methylene or ethylene), substituted hydrocarbylene(e.g., substituted methylene or substituted ethylene), heterocyclic,carboxyalkyl (—CO₂-alkyl), carboxamidoalkyl (—CON-alkyl), or aminoalkyl.In each of these embodiments in which a hydrocarbyl(ene) or heterocyclicmoiety is substituted, a carbon atom is substituted with a hetero atomsuch as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or ahalogen atom; thus, for example, the hydrocarbyl(ene) or heterocyclicmoiety may be substituted with halogen, heterocyclo, alkoxy, alkenoxy,alkynoxy, or aryloxy. In each of these embodiments of the polymer ofFormula I, n is preferably at least 10, or at least 20, or at least 40,or at least 100, or at least 400, or at least 1000, or at least 4000, orat least 10,000. In the polymer of Formula I, n can preferably rangefrom 4 to 100,000, and preferably from 10 to 10,000.

In various embodiments, R₁ or R₂ have the formula—(CH₂)_(m)—HET-(R_(x))_(t) or the formula —(CH₂)_(m)—Ar—(R_(x))_(t) andt is 1-5; additionally, R_(x) may be C₁-C₁₈ alkyl. Further, R₁ or R₂ maycorrespond to Formula VI

wherein m is 0 to 10; R_(x) is linear or branched C₁-C₁₈ alkyl, C₁-C₁₈alkenyl, C₁-C₁₈ alkynyl, or C₁-C₂₀ aryl; and t is 0 to 5. In someembodiments, the (alk)aryl group corresponding to Formula VI is otherthan benzyl. Preferably, when R₁ or R₂ corresponds to Formula VI, R_(x)is linear or branched C₁-C₁₈ alkyl or C₁-C₁₈ alkenyl; more preferablyC₁-C₃ alkyl or C₁-C₃ alkenyl. In various preferred embodiments, when R₁or R₂ corresponds to Formula VI, m is 1 to 3 and when m is 1 to 3, t is1.

Preferred polymers of Formula I include:

Other examples of preferred polymers of Formula I include each of thestructures shown in the previous paragraph with alternative alkyl group(e.g., ethyl, propyl, butyl, pentyl, hexyl, etc.) substituted formethyl. Other preferred polymers of Formula I include:

wherein HET is heterocyclic, Ar is aryl, R_(x) is optionally substitutedalkyl, alkenyl, alkynyl or aryl, m is 0 to 10; and t is 1 to 5. In someembodiments, m is 1 to 10.

Even more preferred polymers of Formula I include:

In a second embodiment, the polymer can be characterized as a polymer orpreferably a crosslinked polymer, in each case where the polymer isrepresented by Formula II:

or a copolymer thereof, wherein n is at least 4; R₁, R₂, and R₃ areindependently selected from hydrogen, alkyl, phenyl, aryl, orheterocyclic or a moiety —C(═NH)—NH2; X are independently selected fromhydroxide, halid, sulfonate, sulfate, carboxlate, and phosphate; A is alinker wherein A is nothing or is selected from alkyl, aryl,heterocyclic, carboxyalkyl (—CO₂-alkyl), carboxamidoalkyl (—CON-alkyl),or aminoalkyl. In one embodiment, R₁, R₂ and R₃ are independentlyselected from hydrogen, hydrocarbyl, substituted hydrocarbyl,heterocyclic and the residue of a crosslinking agent or, R₁ and R₂together, in combination with the nitrogen atom to which they arebonded, form a heterocylic (i.e., a vinylheterocyclic). For example, inthis embodiment R₁, R₂ and R₃ may be independently selected fromhydrogen, optionally substituted alkyl, alkenyl, alkynyl,(alk)heterocyclic or (alk)aryl wherein (alk)heterocylic has the formula—(CH₂)_(m)—HET-(R_(x))_(t), (alk)aryl has the formula—(CH₂)_(m)—Ar—(R_(x))_(t), m is 0-10, t is 0-5, HET is a heterocyclicmoiety, Ar is an aryl moiety, and R_(x) is hydrocarbyl or substitutedhydrocarbyl. When R₁, R₂, or R₃ is —(CH₂)_(m)—HET-(R_(x))_(t) and theheterocyclic moiety, HET, is heteroaromatic or, when R₁, R₂ or R₃ is—(CH₂)_(m)—Ar—(R_(x))_(t), it is sometimes preferred that m be atleast 1. In addition, when R₁, R₂ or R₃ is —(CH₂)_(m)—Ar—(R_(x))_(t) andm is 1, it is sometimes preferred that t be at least 1. Further, whenone of R₁ R₂ and R₃ is —(CH₂)_(m)—Ar—(R_(x))_(t) or—(CH₂)_(m)—HET-(R_(x))_(t), it is sometimes preferred that the others behydrogen, lower alkyl (e.g., methyl, ethyl or propyl) or the residue ofa crosslinking agent. In one embodiment, R₁ and R₃ are optionallysubstituted alkyl and R₂ is —(CH₂)_(m)—HET-(R_(x))_(t) or—(CH₂)_(m)—Ar—(R_(x))_(t), wherein m is 0-10, t is 0-5, HET is aheterocyclic moiety, Ar is an aryl moiety, and R_(x) is hydrocarbyl orsubstituted hydrocarbyl. In another embodiment, R₁, R₂ and R₃ may behydrogen, optionally substituted alkyl, —(CH₂)_(m)—HET-(R_(x))_(t) or—(CH₂)_(m)—Ar—(R_(x))_(t), and A is hydrocarbylene (e.g., methylene orethylene), substituted hydrocarbylene (e.g., substituted methylene orsubstituted ethylene), heterocyclic, carboxyalkyl (—CO₂-alkyl),carboxamidoalkyl (—CON-alkyl), or aminoalkyl. In each of theseembodiments in which a hydrocarbyl(ene) or heterocyclic moiety issubstituted, a carbon atom is substituted with a hetero atom such asnitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogenatom; thus, for example, the hydrocarbyl(ene) or heterocyclic moiety maybe substituted with halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, oraryloxy. In each of these embodiments of Formula II, n is preferably atleast 10, or at least 20, or at least 40, or at least 100, or at least400, or at least 1000, or at least 4000, or at least 10,000. In thepolymer of Formula II, n can preferably range from 4 to 100,000, andpreferably from 10 to 10,000.

Preferred polymers of Formula II include:

Even more preferred polymers of Formula II include:

The aforementioned polyvinylamine polymers are exemplary, and notlimiting. Other preferred polyvinylamine polymers will be apparent to aperson of skill in the art.

In one embodiment, the shell is a polymer containing repeat unitsderived from an alkyleneimine monomer, such as ethyleneimine orpropyleneimine monomers.

A polyalkyleneimineamine shell polymer can, in one embodiment, becharacterized as a polymer or preferably a crosslinked polymer, in eachcase where the polymer is represented by Formula IV:

or a copolymer thereof, wherein n is at least 2, R₁ is selected fromhydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and theresidue of crosslinking agents, and R₁₁ and R₁₂ are independentlyhydrogen, alkyl or aryl. In one embodiment, z is 2 to 10; for example,when z is 2, the repeat unit is an ethyleneimine repeat unit and when zis 3, the repeat unit is a propyleneimine repeat unit. In a preferredembodiment, R₁₁ and R₁₂ are hydrogen or alkyl (e.g., C1-C3 alkyl); inone particular preferred embodiment, R₁₁ and R₁₂ are hydrogen or methyland z is 2 or 3. In each of these embodiments, R₁ may be, for example,selected from hydrogen, optionally substituted alkyl, alkenyl, alkynyl,(alk)heterocyclic or (alk)aryl wherein (alk)heterocylic has the formula—(CH₂)_(m)—HET-(R_(x))_(t), (alk)aryl has the formula—(CH₂)_(m)—Ar—(R_(x))_(t), m is 0-10, t is 0-5, HET is a heterocyclicmoiety, Ar is an aryl moiety, and R_(x) is hydrocarbyl or substitutedhydrocarbyl. When R₁—(CH₂)_(m)—HET-(R_(x))_(t) and the heterocyclicmoiety, HET, is heteroaromatic or, when R₁ is —(CH₂)_(m)—Ar—(R_(x))_(t),it is sometimes preferred that m be at least 1. In addition, when R₁ is—(CH₂)_(m)—Ar—(R_(x))_(t) and m is 1, it is sometimes preferred that tbe at least 1. In one embodiment, R₁ is —(CH₂)_(m)—HET-(R_(x))_(t) or—(CH₂)_(m)—Ar—(R_(x))_(t), wherein m is 0-10, t is 0-5, HET is aheterocyclic moiety, Ar is an aryl moiety, and R_(x) is hydrocarbyl orsubstituted hydrocarbyl. In each of these embodiments in which ahydrocarbyl(ene) or heterocyclic moiety is substituted, a carbon atom issubstituted with a hetero atom such as nitrogen, oxygen, silicon,phosphorous, boron, sulfur, or a halogen atom; thus, for example, thehydrocarbyl(ene) or heterocyclic moiety may be substituted with halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, or aryloxy. In each of theseembodiments of the polymer of Formula IV, n is preferably at least 10,or at least 20, or at least 40, or at least 100, or at least 400, or atleast 1000, or at least 4000, or at least 10,000. In the polymer ofFormula IV, n can preferably range from 4 to 100,000, and preferablyfrom 10 to 10,000.

A polyalkyleneimineamine shell polymer can also, in one embodiment, becharacterized as a polymer or preferably a crosslinked polymercontaining quaternary ammonium repeat units, in each case where thepolymer is represented by Formula V:

or a copolymer thereof, wherein n is at least 2, R₁ and R₂ areindependently selected from hydrocarbyl, substituted hydrocarbyl,heterocyclic and the residue of crosslinking agents, R₁₁ and R₁₂ areindependently hydrogen, alkyl or aryl, and X⁻ is anion (preferablyindependently selected from hydroxide, halid, sulfonate, sulfate,carboxlate, and phosphate). In one embodiment, z is 2 to 10; forexample, when z is 2, the repeat unit is an ethyleneimine repeat unitand when z is 3, the repeat unit is a propyleneimine repeat unit. In apreferred embodiment, R₁₁ and R₁₂ are hydrogen or alkyl (e.g., C1-C3alkyl); in one particular preferred embodiment, R₁₁ and R₁₂ are hydrogenor methyl and z is 2 or 3. In each of these embodiments, R₁ and R₂ maybe independently selected from optionally substituted alkyl, alkenyl,alkynyl, (alk)heterocyclic or (alk)aryl wherein (alk)heterocylic has theformula —(CH₂)_(m)—HET-(R_(x))_(t), (alk)aryl has the formula—(CH₂)_(m)—Ar—(R_(x))_(t), m is 0-10, t is 0-5, HET is a heterocyclicmoiety, Ar is an aryl moiety, and R_(x) is hydrocarbyl or substitutedhydrocarbyl. When R₁ or R₂ is —(CH₂)_(m)—HET-(R_(x))_(t) and theheterocyclic moiety, HET, is heteroaromatic or, when R₁ or R₂ is—(CH₂)_(m)—Ar—(R_(x))_(t), it is sometimes preferred that m be atleast 1. In addition, when R₁ or R₂ is —(CH₂)_(m)—Ar—(R_(x))_(t) and mis 1, it is sometimes preferred that t be at least 1 (e.g., that the(alk)aryl moiety be other than benzyl). Further, when one of R₁ and R₂is —(CH₂)_(m)—Ar—(R_(x))_(t) or —(CH₂)_(m)—HET-(R_(x))_(t), it issometimes preferred that the other be hydrogen, lower alkyl (e.g.,methyl, ethyl or propyl) or the residue of a crosslinking agent. In oneembodiment, R₁ is hydrocarbyl or substituted hydrocarbyl, and R₂ is—(CH₂)_(m)—HET-(R_(x))_(t) or —(CH₂)_(m)—Ar—(R_(x))_(t), wherein m is0-10, t is 0-5, HET is a heterocyclic moiety, Ar is an aryl moiety, andR_(x) is hydrocarbyl or substituted hydrocarbyl. In each of theseembodiments in which a hydrocarbyl(ene) or heterocyclic moiety issubstituted, a carbon atom is substituted with a hetero atom such asnitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogenatom; thus, for example, the hydrocarbyl(ene) or heterocyclic moiety maybe substituted with halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, oraryloxy. In each of these embodiments of the polymer of Formula V, n ispreferably at least 10, or at least 20, or at least 40, or at least 100,or at least 400, or at least 1000, or at least 4000, or at least 10,000.In the polymer of Formula V, n can preferably range from 4 to 100,000,and preferably from 10 to 10,000.

The shell polymer can, in some preferred embodiments, comprise acopolymer comprising two or more polymers having different monomerrepeat units, where (i) at least one of the polymers is a crosslinked ornon-crosslinked polymer represented by Formula I, or (ii) at least oneof the polymers is a crosslinked or non-crosslinked polymer representedby Formula II, or (iii) at least one of the polymers is a crosslinked ornon-crosslinked polymer represented by Formula I and at least one of thepolymers is a crosslinked or non-crosslinked polymer represented byFormula II.

In some embodiments, the polyvinylamine polymer can be avinylheterocyclic amine polymer, such as polymers having repeat unitsselected from a group consisting of vinylpyridines, vinylimidazoles,vinyl pyrrazoles, vinylindoles, vinyltriazoles, vinyltetrazoles, as wellas alkyl derivatives thereof, and combinations therof. For example,polyvinylamine shell polymer can be a polymer having repeat unitsselected from vinylpyridines, vinylimidazole, vinylindoles, includingfor example polymers represented by one or more of Formula IIIA throughIIIE:

wherein in each case n is at least 4. The compounds of Formulas IIIAthrough IIIE can optionally be substituted or derivatized to include oneor more additional moieties (not shown in the formulas), for examplewith an R-group on the heterocycle, where such moieties areindependently selected from hydrogen, alkyl, phenyl, aryl, orheterocyclic, hydroxide, halide, sulfonate, sulfate, carboxlate, andphosphate. In the polymer of Formulas IIIA through IIIE, n is preferablyat least 10, or at least 20, or at least 40, or at least 100, or atleast 400, or at least 1000, or at least 4000, or at least 10,000. Inthe polymer of Formula I, n can preferably range from 4 to 100,000, andpreferably from 10 to 10,000.

In some embodiments, the polyamine polymer can comprise apolybenzylamine polymer.

In some embodiments, the polyamine polymer can comprise cyclopolymers,for example as formed from diallyl amine monomers. Preferred polymersinclude

wherein n is at least 4; R are independently selected from hydrogen,alkyl, phenyl, aryl, or heterocyclic; X are independently selected fromhydroxide, halide, sulfonate, sulfate, carboxlate, and phosphate. n ispreferably at least 10, or at least 20, or at least 40, or at least 100,or at least 400, or at least 1000, or at least 4000, or at least 10,000.

In some embodiments, the amine polymers can comprise a guanilylatedcompound. In some embodiments, for example, polyvinylamine moieties(e.g., as disclosed herein) can have a guanylated counterpart producedby treatment of he prescursor amine moiety with, for example, pyrazzoleguanidine. For example, such treatment could proceed by a mechanismrepresented schematically as follows:

The polyvinylic (e.g., polyvinylamine) polymer can have a weight averagemolecular weight or a number average molecular weight of at least(about) 1000, preferably at least (about) 10,000. In any suchembodiment, the polyvinylic polymer can have a weight average molecularweight or a number average molecular weight ranging from (about) 1,000to (about) 2,000,000, preferably from (about) 1,000 to (about)1,000,000, or from (about) 10,000 to (about) 1,000,000, and preferablyfrom (about) 10,000 to (about) 500,000. Preferably, the polyvinylic(e.g., polyvinylamine) polymer can have a polydispersity index (PDI)ranging from (around) 1 to 10, and preferably ranging from 1 to 5, orfrom 1 to 2.

The shell component can comprise, in some embodiments, the polyvinylicpolymer (e.g., such as polyvinylamine polymer) as a densely crosslinkedpolyvinylic polymer. In some embodiments, for example, the polyvinylic(e.g., polyvinylamine) polymer can be a product of a crosslinkingreaction comprising crosslinking agent and polyvinylic polymer in aratio of crosslinking agent to crosslinkable functional groups of thepolymer not less than (about) 2:1, and preferably in a ratio rangingfrom (about) 2:1 to (about) 10:1, ranging from (about) 2.5:1 to (about)6:1, or ranging from (about) 3:1 to (about) 5:1 and in some embodimentsin a ratio of (about) 4:1, by mole. In some embodiments, the crosslinkedshell polymer can be a crosslinked polyvinylamine polymer comprising acrosslinking moieties and amine moieties in a ratio of not less than(about) 0.05:1, preferably not less than (about) 0.1:1, and preferablyin a ratio ranging from (about) 0.1:1 to (about) 1.5:1, more preferablyranging from (about) 0.5:1 to (about) 1.25:1, or from (about) 0.75:1 to(about) 1:1, in each case based on mole equivalent of crosslinkingmoiety to amine moiety in the crosslinked polyvinylamine polymer.

The shell polymer can be crosslinked with a crosslinking agent.Generally, the crosslinking agent can be a compound having two or moremoieties reactive with a functional group of the shell polymer.

For shell polymers comprising repeat units having amine functionalgroups, the crosslinking agent can generally be a compound having two ormore amine reactive moieties. Suitable compound having an amine reactivemoiety can include, for example and without limitation, compounds ormoieties selected from epoxides, alkyl halide, benzyl halide,acylhalide, activated olefin, isocyanate, isothiocyanate, activatedester, acid anhydrides, and lactone, etc.

In some embodiments, the shell polymer (e.g., polyvinylic polymer suchas a polyvinylamine polymer) can be crosslinked with a small moleculecrosslinking agent having a molecular weight of not more than (about)500, preferably not more than (about) 300, or not more than (about) 200,or not more than (about) 100. In some embodiments, the shell polymer(e.g., polyvinylic polymer such as a polyvinylamine polymer) can becrosslinked with oligomer or polymer bearing amine reactive moieties.

In preferred embodiments, the crosslinking agent can be selected fromthe group consisting of epoxides, halides, activated esters, isocyanate,anhydrides, and combinations thereof. Suitable crosslinking agentsinclude epichlorohydrine, alkyl diisocyanates, alkyl dihalides, ordiesters. Preferably, the crosslinking agent can be a di-functional ormultifunctional-expoxide, -halide, -isocyanate, -anhydride, -ester andcombinations thereof.

In some embodiments, the crosslinking agent for the shell component canbe a hydrophobic crosslinking agent. For example, the crosslinking agentcan be N,N diglycidylaniline (N,N-DGA), or2,2′-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bis-oxirane, or2,4 diisocyanate (TID), among others.

In some embodiments, the crosslinking agent for the shell component canbe selected from the group consisting of epichlorohydrine (ECH),1,2-bis-(2-iodoethoxy)ethane (BIEE) and N,N diglycidylaniline (N,N-DGA)and combinations thereof.

In some embodiments, the crosslinking agent can be selected from one ormore of the following crosslinking agents (alone or in variouspermutations and combinations):

Crosslinking agents are commercially available, for example, fromcommercial sources, such as Aldrich, Acros, TCI, or Lancaster.

The shell component can be (e.g. situated or formed) over a surface ofthe core component. The shell component can be physically or chemicallyattached (e.g., physically or chemically adhered or bonded) to the corecomponent. In some embodiments for example, the shell component can beadhered to the core component by ionic bonding. In other embodiments forexample, the shell component can be covalently bonded to the corecomponent. As a nonlimiting example, the shell component can becovalently bonded to the core component through ester, amide, orurethane linkages. In some cases, the shell polymer is attached to thecore through physical bonds, chemical bonds, or a combination of both.In the former case, the electrostatic interaction between negativelycharged core and positively charged shell can maintain the core-shellcomposition during use (e.g., during transit in the gastrointestinaltract). In the latter case a chemical reaction can be carried out at thecore-shell interface to form covalent bonds between the crosslinkedshell polymer and the core component.

Shell polymers (generally), such as hydrophilic polymers, polyvinylicpolymers (e.g., polyvinylamine) and other polymers described herein aregenerally commercially available. For example, polyvinylamine polymersare commercially available from BASF (e.g., under the trade nameLupramin). Preferred polyvinylic polymers are described above.

One method for determining the percentage of nitrogen atoms in the solidpolymer that are quaternary ammonium nitrogens is to analyze a sampleusing X-ray photoelectron spectroscopy (XPS). The XPS data generallyindicates the composition of the core-shell particles tested anddifferentiates the primary, secondary, tertiary, and quaternary nitrogenatoms in the amine functional polymer shell. The XPS can generallyfurther distinguish between nitrogen atoms bonded to three organicgroups and protonated from nitrogen atoms bonded to four organic groups.Various polymeric systems containing quaternary ammonium ions havedemonstrated the use of XPS to determine the extent of those nitrogensthat are bonded to four organic groups. (Adv. Polymer Sci. 1993, 106,136-190; Adv. Mater. 2000, 12(20), 1536-1539; Langmuir 2000, 16(26),10540-10546; Chem. Mater. 2000, 12, 1800-1806).

Core Component

The core component generally comprises an organic material (e.g., anorganic polymer) or an inorganic material. Preferably, the corecomponent can comprise a capacity for binding monovalent cation (e.g.,an inorganic monovalent cation such a potassium ion or sodium ion).

Organic core materials preferably include organic polymers, andespecially a polymer having a capacity for binding monovalent cation(e.g., an inorganic monovalent cation), such a potassium ion or sodiumion. Polyacrylic acid polymers, polyhaloacrylic acid polymers,polystyrenic polymers, polysulfonic polymers and polystyrenesulfonatepolymers are preferred core polymers.

Inorganic core materials can include ceramics, microporous andmesoporous materials (e.g. zeolites).

In particularly preferred embodiments, the core component can comprise apolymer selected from a poly-fluoroacrylic acid polymer, apoly-difluoromaleic acid polymer, polysulfonic acid, and combinationsthereof, in each case optionally (and generally preferably) crosslinked.In some preferred embodiments the core-component polymer comprises2-fluoroacrylic acid crosslinked with a crosslinking agent. Thecrosslinking agent for a polymeric core component can be selected fromthe group consisting of divinylbenzene, 1,7-octadiene, 1,6-heptadiene,1,8-nonadiene, 1,9-decadiene, 1,4-divinyloxybutane,1,6-hexamethylenebisacrylamide, ethylene bisacrylamide,N,N′-bis(vinylsulfonylacetyl) ethylene diamine, 1,3-bis(vinylsulfonyl)2-propanol, vinylsulfone, N,N-methylenebisacrylamide polyvinyl ether,polyallylether, and combinations thereof. In some preferred embodiments,the crosslinking agents are selected from divinylbenzene, 1,7-octadiene,1,4-divinyloxybutane, and combinations thereof. In some embodiments, thecore can be in its proton form, sodium form, potassium form, calciumform, ammonium form, or combinations thereof.

Preferred monomer repeat units of the core polymers, such asα-fluoroacrylate and difluoromaleic acid can be prepared from a varietyof routes. See for example, Gassen et al, J. Fluorine Chemistry, 55,(1991) 149-162, K F Pittman, C. U., M. Ueda, et al. (1980).Macromolecules 13(5): 1031-1036. Difluoromaleic acid is preferred byoxidation of fluoroaromatic compounds (Bogachev et al, ZhurnalOrganisheskoi Khimii, 1986, 22(12), 2578-83), or fluorinated furansderivatives (See U.S. Pat. No. 5,112,993). A preferred mode of synthesisof α-fluoroacrylate is given in EP 415214. Other methods comprise thestep-growth polymerization from phosphonate, carboxylic, phosphate,sulfinate, sulfate and sulfonate functionals compounds. High densitypolyphosphonates such as Briquest, marketed by Rhodia, are particularlyuseful.

Another process to produce alpha-fluoroacrylate beads is directsuspension polymerization. Typically, suspension stabilizers, such aspolyvinyl alcohol or polyacrylic acid, are used to prevent coalescenceof particles during the process. It has been observed that the additionof NaCl and/or aqueous phase polymerization inhibitor such as sodiumnitrite (NaNO₂) in the aqueous phase decreased coalescence and particleaggregation. Other suitable salts for this purpose include salts thatsolubilize in the aqueous phase. Other suitable inhibitors for thepurpose include inhibitors that are soluble in the aqueous phase or aresurface active. In this embodiment, water soluble salts are added at aweight % comprised between (about) 0.1 to (about) 10, preferablycomprised between (about) 1 to (about) 7.5 and even more preferablybetween (about) 2.5 to (about) 5. In this embodiment, polymerizationinhibitors are added at a weight ppm comprised between (about) 0 ppm to(about) 500 ppm, preferably comprised between (about) 10 ppm to (about)200 ppm and even more preferably between (about) 50 to (about) 200 ppm.In this embodiment, buffer reagent such as phosphate buffer can also beused to maintain reaction pH. The buffer reagents are added at a weight% comprised between 0 to 2%. It has been observed that in the case ofalpha-fluoroacrylate esters (e.g. MeFA) suspension polymerization, thenature of the free radical initiator plays a role in the quality of thesuspension in terms of particle stability, yield of beads, and theconservation of a spherical shape. Use of water-insoluble free radicalinitiators, such as lauryl peroxide, led to the quasi absence of gel andproduced beads in a high yield. It was found that free radicalinitiators with water solubility lower than 0.1 g/L preferably lowerthan 0.01 g/L led to optimal results. In preferred embodiments, polyMeFAbeads are produced with a combination of a low water solubility freeradical initiator, the presence of salt in the aqueous phase, such asNaCl, and/or the presence of aqueous polymerization inhibitor such assodium nitrite and a buffer solution.

Generally, the core component can comprise a crosslinked core polymer.The core polymers can be crosslinked using a multifunctionalcrosslinking agent. As non-limiting examples, the crosslinking agent fora polymeric core component can be selected from the group consisting ofdivinylbenzene, 1,7-octadiene, 1,6-heptadiene, 1,8-nonadiene,1,9-decadiene, 1,4-divinyloxybutane, 1,6-hexamethylenebisacrylamide,ethylene bisacrylamide, N,N′-bis(vinylsulfonylacetyl) ethylene diamine,1,3-bis(vinylsulfonyl) 2-propanol, vinylsulfone,N,N′-methylenebisacrylamide polyvinyl ether, polyallylether, andcombinations thereof. In some preferred embodiments the crosslinkingagent are selected from divinylbenzene, 1,7-octadiene,1,4-divinyloxybutane, and combinations thereof. In some embodiments, thecore can be in its proton form, sodium form, potassium form, calciumform, ammonium form, or combinations thereof.

Other preferred core polymers are disclosed below.

Binding Capacity

The core-shell particles of the invention have a high binding capacity(and as described below, preferably also a high (and persistent)selectivity and a high retention) for monovalent cation such aspotassium ion and sodium ion.

The core-shell particle of the invention can have an effective amount ofa potassium binding core, such as a potassium binding polymer (e.g., apolymer having a capacity for binding potassium), such that upon beingadministered to a mammal subject, such as a human, the core-shellparticle effectively binds and removes an average of at least (about)1.5 mmol (or 1.5 mEq) or higher of potassium per gm of core-shellparticle. Preferably the binding capacity or amount of potassium boundin vivo in a human (in other mammal of interest) and removed from thehuman (or other mammal) is (about) 2 mmol or more per gm, more preferredis (about) 3 mmol or more per gm, even more preferred is (about) 4 mmolor more per gm, or (about) 5 mmol per gm, or (about) 6 mmol or more pergm, in each case per gm of core-shell particle. In a preferredembodiment, the average binding capacity or average amount of potassiumbound in vivo in a human (in other mammal of interest) can range from(about) 1.5 mmol per gm to (about) 8 mmol per gm, preferably from(about) 2 mmol per gm to (about) 6 mmol per gm, in each case per gm ofcore-shell particle.

In some embodiments, the core-shell particle has an average in vitrobinding capacity for potassium or an average amount of potassium boundof greater than (about) 1.5 mmol/gm of core-shell composite (e.g.,core-shell particle) at a pH of greater than (about) 5.5. In otherpreferred embodiments, the core-shell particle can have an average invitro binding capacity or amount of potassium bound of at least (about)2.0 mmol/gm, preferably greater than (about) 2.0 mmol/gm, such aspreferably at least (about) 2.5 mmol/gm, or at least (about) 3.0mmol/gm, or at least (about) 3.5 mmol/gm or at least (about) 4.0 mmol/gmor at least (about) 4.5 mmol/gm or at least (about) 5.0 mmol/gm, in eachcase where mmol/gm refers to per gram of of core-shell composite (e.g.,core-shell particle), and in each case as determined an in vitro assaymimicing physiological conditions of the gastrointestinal tract.Preferably, the in vitro binding capacity/amount of potassium bound canbe determined from an assay selected from GI Assay No. I, GI Assay No.II, GI Assay No. III, and combinations thereof, in each case as definedand described in detail below.

The core-shell particle of the invention can additionally oralternatively have an effective amount of a sodium binding core, such asa sodium binding polymer (e.g., a polymer having a capacity for bindingsodium), such that upon being administered to a mammal subject, such asa human, the core-shell particle effectively binds and removes anaverage of at least (about) 1.5 mmol (or 1.5 mEq) or higher of sodiumper gm of core-shell particle. Preferably the in vivo sodium bindingcapacity or amount of sodium bound in a human (or other mammal ofinterest) is (about) 2 mmol or more per gm, more preferred is (about) 3mmol or more per gm, even more preferred is (about) 4 mmol or more pergm, or (about) 5 mmol per gm, or (about) 6 mmol or more per gm, in eachcase per gram of core-shell particle. In a preferred embodiment, theaverage in vivo sodium binding capacity or amount of sodium bound in ahuman (or other mammal of interest) ranges (about) 2 mmol to (about) 6mmol per gm, preferably from (about) 3 mmol to (about) 6 mmol per gram,in each case per gram of core-shell particle.

In some embodiments, the core-shell particle has an average in vitrobinding capacity for sodium or amount of sodium bound of greater than(about) 1.0 mmol/gm, or preferably greater than (about) 1.5 mmol/gm ofcore-shell particle at a pH of greater than (about) 2 or in someembodiments at a pH of greater than (about) 5.5. In other preferredembodiments, the core-shell particle can have an average in vitrobinding capacity or amount of sodium bound of at least (about) 2.0mmol/gm, preferably greater than (about) 2.0 mmol/gm, such as preferablyat least (about) 2.5 mmol/gm, or at least (about) 3.0 mmol/gm, or atleast (about) 3.5 mmol/gm or at least (about) 4.0 mmol/gm or at least(about) 4.5 mmol/gm or at least (about) 5.0 mmol/gm, in each case wheremmol/gm refers to per gram of of core-shell composite (e.g., core-shellparticle), and in each case as determined an in vitro assay mimicingphysiological conditions of the gastrointestinal tract. Preferably, thein vitro binding capacity or amount of sodium bound can be determinedfrom an assay selected from GI Assay No. I, GI Assay No. II, GI AssayNo. III, and combinations thereof, in each case as defined and describedin detail below.

Typically, in vivo binding capacity or amount of ion bound (e.g., aspecific binding for a particular ion) is determined in a mammal such asa human. Techniques for determining in vivo potassium or sodium bindingcapacity in a human are well known in the art. For example, followingadministration of a potassium-binding or sodium-binding polymer to apatient, the amount of potassium or sodium in the feces can be comparedto the amount of the ion found in the feces of subjects who to whom thepolymer has not been administered. The increase in the ion excreted inthe presence of the polymer versus in its absence can be used tocalculate the in vivo potassium or sodium binding per gram of core-shellparticle. The average in vivo binding is preferably calculated in a setof normal human subjects, this set being (about) 5 or more humansubjects, preferably (about) 10 or more human subjects, even morepreferably (about) 25 or more human subjects, and most preferably(about) 50 or more human subjects, and in some instances even 100 ormore human subjects.

The binding of potassium or sodium to the core shell particles, in thepresence of interfering divalent ions and other species, can also bedetermined in vitro. It is preferred that the in vitro potassium orsodium binding is determined in conditions that mimic the physiologicalconditions of the gastro-intestinal tract, in particular the colon.Generally, the in vitro binding capacity/specific binding for aparticular monovalent ion of interest can be determined from an assayselected from GI Assay No. I, GI Assay No. II, GI Assay No. III, andcombinations thereof, in each case as defined and described in detailbelow.

The higher monovalent ion binding of the polymeric core-shell particlesor composition enables the administration of a lower dose of thecomposition, to remove a therapeutically beneficial amount of sodium orpotassium, as described below.

Selectivity/Permselectivity

Advantageously, core-shell particles of the invention are selective tomonovalent cations over divalent cations. Such selectivity is preferablypersistent over a meaningful period, including over a period allowingfor effective application of the compositions and methods of theinvention for treatment of various conditions and/or disorders asdescribed below.

Without being bound by theory not specifically recited in the claims,the crosslinked polyvinylic (e.g., polyvinylamine) shell polymermodulates entry of competing solutes such as magnesium and/or such ascalcium across the shell to the core component. The crosslinked shellpolymer is permselective for inorganic monovalent cations over inorganicdivalent cations. Competing cations have a lower permeability from theexternal environment across the shell compared to that of monovalentions such as potassium ion or sodium ion. Examples of such competingcations include, but are not limited to, Mg⁺⁺, Ca⁺⁺, and protonatedamines. In some embodiments, the shell is permeable to both mono- anddi-valent cations; however, the core-shell particle remains selectivefor binding of monovalent cations due to difference in permeationrates—i.e., due to kinetics affecting the rate of permeation—rather thanas a result of an equilibrium preference for binding of the monovalentcation.

The relative permeability of the shell polymer for monvalent ion versusdivalent ion can be characterized by a permeability ratio ofpermeability for monovalent ions (e.g., potassium ions) to permeabilityfor divalent cations (e.g., Mg⁺⁺ and Ca⁺⁺), as measure in suitableenvironment-representative in vitro assays. For example, as measured ingastrointestinal representative assays, the permeability ratio can rangefrom (about) 1:0.5 to (about) 1:0.0001 (i.e., from (about) 2:1 to(about) 10,000:1), and can preferably range from (about) 1:0.2 and(about) 1:0.01 (i.e., from (about) 5:1 to (about) 100:1). Furtherdetails on methods for determining permeability are disclosed below.

Permselectivity of the crosslinked polyvinylic polymers, such ascrosslinked polyvinylamine, for inorganic monovalent ion over inorganicdivalent ion can, generally be engineered and optimized (i.e., tuned)for an environment of interest. In particular, the shell component canbe adapted to have a reduced permeability for higher valency cations(divalent cations such as magnesium ion and calcium ion) compared topermeability for monovalent cations, for an environment in which thecore-shell particles will be applied. Generally, the permeability of theshell polymer to alkaline-earth cations can be altered by changing theaverage pore size, charge density and hydrophobicity of the membrane.Further details regarding approaches for tuning permselectivity (as wellas persistence, discussed hereinafter, are set forth below.

Retention/Persistence

Preferably, the core-shell particles and compositions comprising suchcore-shell particles (e.g., such as potassium binding polymericcompositions and sodium-binding polymeric compositions described herein)bind the target inorganic monovalent ion and retain the target ion for ameaningful period within the environment of interest. For example, inapplications involving binding of potassium ion or sodium ion in thegastrointestinal tract, the core-shell particle can bind potassium ionor sodium ion in the regions of the gastrointestinal tract having arelatively high concentration of potassium ion or sodium ion,respectively. Such bound potassium ion or sodium ion preferably remainsbound to the core-shell particles and is excreted out of the body, insufficient quantity to have a therapeutic benefit. From an alternativeperspective, the core-shell particles do not significantly release thebound monovalent cation in the environment of interest such as in thegastrointestinal tract, prior to obtaining a desired beneficial effect.The core-shell particles and compositions described herein can retain asignificant amount of the bound monovalent ion such as potassium ion orsodium ion. The term “significant amount” as used herein is not intendedto mean that the entire amount of the bound potassium is retained. It ispreferred that at least some of the bound monovalent ion is retained,such that a therapeutic and/or prophylactic benefit is obtained.Preferred amounts of bound monovalent ion that can be retained rangefrom (about) 5% to (about) 100%, relative to amount initially bound. Itis preferred that the polymeric compositions retain (about) 25% of thebound monovalent ion, more preferred is (about) 50%, even more preferredis (about) 75% and most preferred is retention of (about) 100% of thebound monovalent ion.

The period of retention is generally preferred to be during the timethat the core-shell particle or composition is being used, in theenvironment of interest. For example, for applications involving ionbinding in the gastrointestinal tract the time is a period sufficientfor a therapeutically and/or prophylactically beneficial effect. In theembodiment in which the composition is used to bind and removemonovalent ion from the gastrointestinal tract, the retention period canbe generally the time of residence of the composition in thegastro-intestinal tract and more particularly the average residence timein the colon.

Advantageously, the selectivity (e.g., permselectivity) of thecore-shell particles of the invention is sufficiently persistent to havea beneficial effect, such as a beneficial prophylactic or a beneficialtherapeutic effect. The persistent selectivity (e.g. persistentpermselectivity) of the core-shell particles is particularlyadvantageous for binding monovalent ions, and especially for bindingpotassium ion, in the gastrointestinal tract. The persistent selectivity(e.g. persistent permselectivity) of the core-shell particles is alsoadvantageous for binding sodium ion in the gastrointestinal tract.

Notably, the gastrointestinal tract comprises a substantially diverseset of environments—particularly with respect to cation concentration.The concentration of cations varies substantially in the stomach and inthe small intestine according to diet. However, estimates can be drawnbased on average diets. See, for example, Hunt, C. D. et al., “Aluminum,boron, calcium, copper, iron, magnesium, manganese, molybdenum,phosphorus, potassium, sodium, and zinc: concentrations in commonwestern foods and estimated daily intakes by infants; toddlers; and maleand female adolescents, adults, and seniors in the United States.” J AmDiet Assoc 101(9): 1058-60 (2001). See also USDA National NutrientDatabase for Standard References, Release 16-1. Generally, in the smallintestine (e.g., as measured at the end of the ileum), sodium ion andpotassium ion concentration approximate the concentration of these ionsin serum (as physiologically regulated), whereas calcium ion andmagnesium ion depend on diet and secretion, and therefore vary over awider range. Ion concentrations in the lower colon (e.g., sigmoid colon)are generally known. See, for example, Wrong, O., A. Metcalfe-Gibson, etal. (1965). “In Vivo Dialysis of Faeces as a Method of Stool Analysis.I. Technique and Results in Normal Subjects.” Clin Sci 28: 357-75. Seealso, Wrong, O. M. (1971). “Role of the human colon in Homeostasis.”Scientific Basis of Medicine: 192-215. See also, Salas-Coll, C. A., J.C. Kermode, et al. (1976). “Potassium transport across the distal colonin man.” Clin Sci Mol Med 51(3): 287-96. See also Agarwal, R., R.Afzalpurkar, et al. (1994). “Pathophysiology of potassium absorption andsecretion by the human intestine.” Gastroenterology 107(2): 548-71.

Table 1 shows typical concentrations of various inorganic monovalent anddivalent cations at various regions of the gastrointestinal tract, asreported in literature.

TABLE 1 [Na+] [K+] [Mg++] [Ca++] pH Stomach* ~30 mM ~15 mM    ~5 mM  ~10 mM 2-6   Ileum ~120 mM   ~5 mM ~10-50 mM ~10-50 mM 7-7.5 Sigmoid~30 mM ~75 mM ~20-40 mM ~10-40 mM 6-7.5 Colon *values are dietdependent; reported ranges based on US average diet.

With respect to monovalent cation binding, for example: hydrogen ion isespecially prevalent in the stomach (e.g. gastric acids); sodium ion isparticularly prevalent in the ileum and earlier regions of the colon(e.g., ascending colon), but is less prevalent in the latter regions ofthe colon (e.g., descending colon and Sigmoid colon) (See, e.g., Ross,E. J. et al. “Observations on cation exchange resins in the small andlarge intestines.” Clin Sci (Lond) 13(4): 555-66 (1954); see alsoSpencer, A. G. et al., “Cation exchange in the gastrointestinal tract.”Br Med J 4862: 603-6 (1954)); and potassium ion is particularlyprevalent in latter regions of the colon (e.g. descending colon andSigmoid colon) (See, e.g., Wrong, O., A. et al., “In Vivo Dialysis ofFaeces as a Method of Stool Analysis. I. Technique and Results in NormalSubjects.” Clin Sci 28: 357-75 (1965); see also Wrong, O. M., “Role ofthe human colon in Homeostasis.” Scientific Basis of Medicine: 192-215(1971); see also Salas-Coll, C. A. et al., “Potassium transport acrossthe distal colon in man.” Clin Sci Mol Med 51(3): 287-96 (1976); seealso Agarwal, R., R. et al., “Pathophysiology of potassium absorptionand secretion by the human intestine.” Gastroenterology 107(2): 548-71(1994).)

Divalent cations, such as Mg++ and Ca++ are generally prevalentthroughout the small intestine and the colon (See Shiga, A., T. et al.,“Correlations among pH and Mg, Ca, P, Na, K, Cl— and HCO3-contents ofdigesta in the gastro-intestinal tract of rats.” Nippon Juigaku Zasshi49(6): 973-9 (1987); see also McCarthy, J. et al., “Divalent CationMetabolism: Calcium”, in Atlas of Diseases of the Kidney. Vol. 1. R. W.Schrier, editor. Blackwell Sciences, Philadelphia (1999); see alsoMcCarthy, J. et al., “Divalent Cation Metabolism: Magnesium” in Atlas ofDiseases of the Kidney. Vol. 1. R. W. Schrier, editor. BlackwellSciences, Philadelphia (1999)).

Persistent Selectivity—Potassium

Significantly, the compositions (e.g., pharmaceutical compositions) andthe core-shell particles of the present invention selectively bindpotassium ion over competing inorganic divalent ions such as magnesiumand/or calcium, and the selectivity is persistent. The persistentselectivity of the compositions (and the core-shell particles) of theinvention for potassium ion over one or more divalent ions (e.g.,magnesium ion, calcium ion) is realized by effectively reducing (e.g.,substantially minimizing, retarding or precluding) the extent of bindingof inorganic divalent ions (especially magnesium ion and/or calciumion), and maintaining such reduced extent of binding over a period oftime meaningful for the application of interest. For example, inapplications involving potassium-ion binding in the gastrointestinaltract, the portion of the binding capacity (e.g., on a cation exchangeresin) occupied by such divalent ions is preferably minimized (orprecluded) over a period of time required for the composition to transitthe small intestine and the colon, where divalent ions such as magnesiumion and calcium ion are prevalent. Notably, divalent cations arepreferentially bound by cation exchange resins (e.g., by a corecomponent comprising a cation exchange resin as a core polymer) incomparison to monovalent cations; as such, the significance of divalentions as interferents for monovalent ion binding is substantial, and isnot directly correlated to relative concentration of divalent ion versusmonovalent ion. In preferred embodiments, such persistent selectivityover divalent ions is realized, for example, using a permselective shellover a potassium-binding core, where the shell has a persistentpermselectivity for potassium over inorganic divalent ion, includingmagnesium ion and/or calcium ion.

Also significantly, in applications for core-shell particles andcompositions in the gastrointestinal tract, the core-shell particles andcompositions of the invention can be effective for removing potassiumpreferentially (even over potentially-competing sodium ion) from thegastrointestinal tract, based on a capability to exchange monovalentions relatively quickly from the core-shell particle. Specifically, thecore-shell particles and compositions can be effective for bindingpotassium ion, based on the relative concentrations of potassium andsodium in various regions of the gastrointestinal environment coupledwith a capability to bind potassium ion at a rate that allows a cationexchange resin to become preferentially loaded with potassium ion oversodium ion in regions of the gastrointestinal environment wherepotassium ion concentration exceeds sodium ion concentration. Inparticular, the core-shell particles and compositions of the inventioncan be effective for binding potassium ion preferentially over competingsodium ion in the lower colon (e.g., distal colon), preferably withinthe period of time the composition resides in the lower colon. In thegastrointestinal tract, sodium ion is present in relatively highconcentrations compared to potassium ion in the small intestine (e.g.,ileum); however, the relationship inverts as the composition transitsfurther down the gastrointestinal tract—with potassium ion present inrelatively high concentrations compared to sodium ion in the lower colon(e.g., distal colon). Hence, a monovalent cation exchange resin canpreferentially bind potassium over sodium in the gastrointestinal tractif the exchange kinetics for potassium are sufficiently fast to allowfor meaningful potassium binding within the period of passage throughthe lower colon (e.g., the distal colon).

Accordingly, the compositions (and core-shell particles) of the presentinvention are preferably applied as potassium binders, and especially inthe gastrointestinal tract of a mammal.

In a preferred embodiment, the compositions (and core-shell particles)of the invention bind a greater amount of potassium ion than sodium ion(within a potassium-binding period representative of the transit timefor the lower colon), and also have a persistent selectivity forpotassium ion over one or more divalent ions, e.g., magnesium ion,calcium ion (over a divalent ion-binding period representative of thetransit time through the gastrointestinal tract or a relevant portionthere of (e.g., through the small intestine and the colon)). Forexample, in one embodiment, the composition can comprise a core-shellparticle comprising a core component and a shell component. The corecomponent can be a polymer having a capacity for binding potassium ion.The shell component can be a persistent permselective polymer forpotassium ion over magnesium ion and/or calcium ion. The composition(and core-shell particle) can be further characterized by (i) binding aneffective amount of potassium ion within a relatively shortpotassium-binding period (e.g., generally less than (about) ten hours),in combination with (ii) retarding binding of divalent cation (e.g.,magnesium ion and/or calcium ion) with such retarded binding maintainedover a relatively long magnesium-binding period and/or calcium-bindingperiod (e.g., generally more than (about) twelve hours).

Generally, for embodiments of the invention in which the core componentcomprises a core polymer which is a cation exchange resin, theion-binding period for a particular ion of interest (e.g., apotassium-binding period for potassium ion) can be understood by aperson of ordinary skill in the art as reflecting a time scale forcation exchange (e.g., a cation-exchange period)—specifically forexample, a time scale for monovalent cation exchange (with respect tomonovalent ion-binding periods), or for example, a time scale fordivalent cation exchange (with respect to divalent ion-binding periods).Also, the reference to “binding” of monovalent or divalent ions in thecontext of such embodiments can be understood by a person of ordinaryskill in the art to mean and include a number of interactions betweenthe cation and the cation exchange media over a period of time, duringwhich particular cations can exchange arbitrarily in response to changesin cation concentration in the environment, and within generallyestablished and understood driving forces to attain (or reattain)equilibrium. Without being bound by theory, a total number of cationswithin an cation exchange media of a core-shell particle issubstantially constant; cations can enter and leave the cation exchangemedia dynamically over time. Within the cation exchange media, cationsmay diffuse freely within the particle, and/or may be associated with afixed charge group for a period of time.

Generally, with regard to the persistent selectivity of the compositionsof the invention, an effective amount of potassium ion is preferablybound to the compositions of the invention within a potassium-bindingperiod of less than (about) six hours, preferably less than (about) fivehours, or less than (about) four hours, or less than (about) threehours, or less than (about) two hours, or less than (about) one hour.Generally, the persistent selectivity of the compositions for potassiumion over inorganic divalent ions (especially magnesium ion and/orcalcium ion) is maintained over a magnesium-binding period and/or over acalcium-binding period of more than (about) 18 hours, preferably morethan (about) 24 hours, more preferably more than (about) 30 hours, andin some embodiments, more than (about) 36 hours, more than (about) 40hours, more than (about) 42 hours, more than (about) 48 hours, or morethan (about) 72 hours. Various combinations of potassium binding periods(preferably low) with magnesium ion biding periods and/or calcium ionbinding periods are contemplated. For example, it is generallypreferable that the potassium-binding period is less than (about) 6hours, and the magnesium-binding period and/or the calcium bindingperiod is more than (about) 18 hours. In some embodiments, thepotassium-binding period is less than (about) 4 hours, and themagnesium-binding period and/or the calcium binding period is more than(about) 24 hours. In some embodiments, the potassium-binding period isless than (about) 2 hours, and the magnesium-binding period and/or thecalcium binding period is more than (about) 30 hours, or 36 hours, or 42hours or 48 hours or 72 hours. In some embodiments, thepotassium-binding period is less than (about) 1 hour, and themagnesium-binding period and/or the calcium binding period is more than(about) 30 hours, or 36 hours, or 42 hours, or 48 hours, or 72 hours.Other combinations are more fully described herein after.

The combination of a persistent selectivity for potassium ion overdivalent ion such as magnesium ion and/or calcium ion, as well as theeffective preferential binding for potassium ion over sodium ion, can bemore specifically characterized, as follows.

In one first approach, for example, the persistent selectivity andpreferential binding can be characterized based on a specific bindingprofile—defined by the extent of binding of potassium ion over time andthe extent of (reduced, retarded or precluded) binding of magnesium ionand/or calcium ion over time. Preferably, for example, the composition(or core-shell particle) can have a specific binding of potassium ion ofat least (about) 1.5 mmol/gm, preferably at least (about) 2.0 mmol/gm or2.5 mmol/gm or 3.0 mmol/gm, or 3.5 mmol/gm or 4.0 mmol/gm or 4.5 mmol/gmor 5.0 mmol/gm, in each case achieved within a potassium-binding periodof less than (about) six hours, and in various combination, thecomposition can have a specific binding of magnesium ion and/or ofcalcium ion of not more than 5.0 mmol/gm, or not more than 4.0 mmol/gmor not more than 3.0 mmol/gm, preferably not more than 2.0 mmol/gm, morepreferably not more than (about) (about) 1.5 mmol/gm, and mostpreferably not more than (about) 1.0 mmol/gm or not more than (about)0.75 mmol/gm or not more than (about) 0.5 mmol/gm, in each casemaintained over a magnesium-binding period and/or a calcium-bindingperiod of more than (about) eighteen hours. The specific binding can bedetermined in vivo or can be determined in vitro using one or more assayprotocols, preferably where such protocols mimic or are representativeof inorganic ion concentrations typical of the gastrointestinal tract,and especially of the lower intestine and/or of the colon. Preferably,the specific binding can be determined using an in vitro assay selectedfrom GI Assay No. I, GI Assay No. II, GI Assay No. III, and combinationsthereof, in each case as described and defined below. Thepotassium-binding period is preferably less than (about) 4 hours, orless than (about) 2 hours, or less than (about) 1 hour, and consideredin various combinations, the magnesium-binding period and/or thecalcium-binding period is preferably more than (about) 24 hours, or morethan (about) 30 hours, or more than (about) 36 hours, or more than(about) 42 hours, or more than (about) 48 hours, or more than 72 hours.For example, in some particularly preferred embodiments, thepotassium-binding period is preferably less than (about) 2 hours, andthe magnesium-binding period and/or the calcium-binding period ispreferably more than (about) 36 hours. In especially preferredembodiments, the potassium-binding period is preferably less than(about) 1 hour, and the magnesium-binding and/or the calcium-bindingperiod period is preferably more than (about) 42 hours.

In another second approach, for example, the persistent selectivity andpreferential binding of the compositions (or the core-shell particles)of the invention can be characterized based on a relative bindingprofile—defined by the relative binding of potassium ion as compared tototal inorganic cation bound as measured over time, and further definedby the relative (reduced, retarded or precluded) binding of magnesiumion and/or calcium ion as compared to total inorganic cation bound overtime. Preferably, for example, the composition (or core-shell particle)can have a relative binding of potassium ion of at least (about) 20% bymole of the total bound cation, preferably at least (about) 30% by moleof the total bound cation, and more preferably of at least (about) 40%by mole of the total bound cation, and even more preferably at least(about) 45% by mole of the total bound cation, or at least (about) 50%by mole of the total bound cation, or at least (about) 55% by mole ofthe total bound cation, or at least (about) 60% by mole of the totalbound cation, or at least (about) 65% by mole of the total bound cation,or at least (about) 70% by mole of the total bound cation, in each caseachieved within a potassium-binding period of less than (about) sixhours, and in various combination, the composition can have a relativebinding of magnesium ion and/or of calcium ion of not more than (about)80% by mole of the total bound cation, preferably not more than (about)70% by mole of the total bound cation, more preferably not more than(about) 60% by mole of the total bound cation, and even more preferablynot more than (about) 40% by mole of the total bound cation, more stillmore preferably not more than (about) 35% by mole of the total boundcation, or not more than (about) 30% by mole of the total bound cation,or not more than (about) 25% by mole of the total bound cation, or notmore than (about) 20% by mole of the total bound cation, or not morethan (about) 15% by mole of the total bound cation, or not more than(about) 10% by mole of the total bound cation, or not more than (about)5% by mole of the total bound cation, in each case maintained over amagnesium-binding period and/or a calcium-binding period of more than(about) eighteen hours. The relative binding can be determined in vivoor can be determined in vitro using one or more assay protocols,preferably where such protocols mimic or are representative of inorganicion concentrations typical of the gastrointestinal tract, and especiallyof the lower intestine and/or of the colon. Preferably, the relativebinding can be determined using an in vitro assay selected from GI AssayNo. I, GI Assay No. II, GI Assay No. III, and combinations thereof, ineach case as described and defined below. The potassium-binding periodis preferably less than (about) 4 hours, or less than (about) 2 hours,or less than (about) 1 hour, and considered in various combinations, themagnesium-binding period and/or the calcium-binding period is preferablymore than (about) 24 hours, or more than (about) 30 hours, or more than(about) 36 hours, or more than (about) 42 hours, or more than (about) 48hours, or more than (about) 72 hours. For example, in some particularlypreferred embodiments, the potassium-binding period is preferably lessthan (about) 2 hours, and the magnesium-binding period and/or thecalcium-binding period is preferably more than (about) 36 hours. Inespecially preferred embodiments, the potassium-binding period ispreferably less than (about) 1 hour, and the magnesium-binding and/orthe calcium-binding period is preferably more than (about) 42 hours.

In a third approach, for example, the persistent selectivity andpreferential binding of the compositions (or the core-shell particles)of the invention can be characterized based on a permselectivityrelative to equilibrium values of ion binding. That is, if thecore-shell particles of the invention are allowed to equilibrate for aperiod of time, the composition (or the core-shell particles) mayeventually bind cations to an extent similar to the core alone. Hence,in one embodiment, the shell component has a permeation rate forpotassium ion sufficiently high to allow potassium ion to achieve a highlevel of binding (but perhaps non-equilibrium level of binding) duringthe mean average residence time in the environment (e.g., in the colon),while the shell component has permeation rate for competing inorganiccations (e.g. Mg²⁺, and/or Ca²⁺) which is lower, such that the competingdivalent cations do not achieve or approach their equilibrium bindinglevels to significant extent during the mean average residence time. Forsuch embodiments, one can define a measure of the time persistence ofpermselectivity. In particular, such time persistence can be the timeneeded to reach between (about) 20% and (about) 80% (i.e., t₂₀, to t₈₀)of the extent of binding at equilibrium in conditions reflecting thecolon electrolyte profile. Preferably, the composition (or core-shellparticle) can have a time persistence for potassium ion (and monovalentcations in general), defined as the time needed to reach (about) 20% or50% or 80% of the equilibrium binding, t₂₀ or t₅₀ or t₈₀, of not morethan (about) six hours, preferably not more than (about) 5 hours, or notmore than (about) 4 hours, or not more than (about) 2 hours, or not morethan (about) 1 hour, and in various combinations, the composition canhave a time persistence for magnesium ion and/or for calcium ion definedas the time needed to reach (about) 20% or 50% or 80% of the equilibriumbinding, t₂₀, or t₅₀ or t₈₀, respectively of more than (about) 18 hours,preferably more than (about) 24 hours, or more than (about) 30 hours, ormore than (about) 36 hours, or more than (about) 40 hours, or more than(about) 42 hours, or more than (about) 48 hours, or more than (about) 72hours. In this approach, the extent of binding and the equilibriumbinding can be determined in vivo or can be determined in vitro usingone or more assay protocols, preferably where such protocols mimic orare representative of inorganic ion concentrations typical of thegastrointestinal tract, and especially of the lower intestine and/or ofthe colon. Preferably, the extent of binding and the equilibrium bindingcan be determined using an in vitro assay selected from GI Assay No. I,GI Assay No. II, GI Assay No. III, and combinations thereof, in eachcase as described and defined below. As applied to determiningequilibrium values, such assays be extended to run over a long period oftime, preferably at least until the earlier of (i) the time at which nofurther changes in supernatant ion concentrations can be detected over acontinuous twenty-four hour period, or (ii) two weeks.

Persistent Selectivity—Sodium

Additionally, the compositions or core-shell particles (e.g.,pharmaceutical compositions) of the present invention can selectivelybind sodium ion over competing inorganic divalent ions such as magnesiumand/or calcium. In general, sodium ion selectivity generally, andpersistent selectivity for sodium ion, in each case over such divalentions, can be based on and characterized in the same manner as describedabove in connection with the selectivity and persistence for potassiumion.

In some applications for core-shell particles and compositions forbinding sodium in the gastrointestinal tract, the core-shell particlesand compositions of the invention may preferentially bind sodium ionover competing potassium ion, particularly in the small intestine wheresodium is especially prevalent—and typically at concentrationssubstantially greater than potassium ion. In such applications, thecore-shell particles and compositions of the invention can comprise acore component and a shell component. The core component can be apolymer having a capacity for binding sodium ion. The shell componentcan be a persistent permselective polymer over magnesium ion and/orcalcium ion (having a permeability for sodium ion that is higher than apermeability for magnesium ion and/or calcium ion). The composition (andcore-shell particle) can be further characterized by one or more of thefollowing, in various combination: (i) having a capacity for binding aneffective amount of sodium ion within a relatively short sodium-bindingperiod representative of the transit time through the small intestine(e.g., generally less than (about) twelve hours); (ii) having apersistent selectivity for retarding (or precluding) binding of divalentcation (e.g., magnesium ion and/or calcium ion) with such retarded (orprecluded) binding maintained over a relatively long magnesium-bindingperiod and/or calcium-binding period representative of the transit timethrough the small intestine and colon (e.g., generally more than (about)twelve hours); and (iii) the shell polymer having a permeability forcompeting inorganic monovalent ions (e.g., potassium) preferably alsofor competing divalent ions (e.g., magnesium ion and/or calcium ion)that is effectively modulated by an environment of the gastrointestinaltract (e.g., such as pH at (about) where the composition moves from thesmall intestine to the colon—where pH typically drops from approximatelypH 7.5 to approximately pH 5.5; or e.g., such as pH at (about) where thecomposition moves from the stomach to the small intestine or such as theincrease in pH from the entrance of the small intestine (duodenum) tothe end of the small intestine (terminal ileum)), such that further ionexchange (e.g., transport through the shell component) between thesodium-binding core and the environment is substantially reduced oreliminated at and beyond a region of the GI tract, beyond which thesodium concentration decreases from its high value in the smallintestine.

Further details and description regarding modulating the permeability ofthe shell component are provided in the following related applications:U.S. application Ser. No. 11/095,918 filed Mar. 30, 2004, which is acontinuation-in-part of U.S. application Ser. No. 10/814,749 filed Mar.30, 2004.

Robustness.

The core-shell particles of the invention are preferably sufficientlyrobust to survive in the environment of intended use. In oneapplication, for example, the core-shell particles are sufficientlyrobust to pass through the gastrointestinal system (or an in-vitro assayrepresentative thereof)—without substantially disintegrating such coreshell particle. In preferred embodiments, the shell component of thecore-shell composition is essentially robust (e.g., not disintegrated,torn, and/or delaminated) under physiological conditions of thegastrointestinal tract (or in vitro representations or mimics thereof)during a period of time for residence and passage through thegastro-intestinal tract. For example, core-shell particle and the shellcomponent of the core-shell particle is essentially not disintegratedunder in vitro conditions selected from the group consisting of (i) anaqueous solution having a pH of (about) 3 over a period of (about) 6hours, (ii) an aqueous solution having a pH of (about) 8 over a periodof (about) 10 hours, (iii) an aqueous solution having a pH of (about) 6over a period of (about) 20 hours and combinations thereof, in each caseat a temperature of (about) 37° C. with agitation.

In some embodiments, the core-shell particles can be robust—with respectto other aspects in addition to not disintegrating, including forexample with respect to physical characteristics and/or performancecharacteristics. Physical characteristics can include particle size,particle size distribution, and/or surface properties, for example, asevaluated visually using microscopes, such as electron microscopesand/or confocal microscopes. Performance characteristics can includespecific binding capacity, selectivity (e.g., permselectivity) andpersistence. Some preferred in vitro assays that can be used inconnection with determining robustness, for example for purposes oftuning a core-shell particle in that regard, include GI Assay No. I, GIAssay No. II, GI Assay No. III, and combinations thereof, in each caseas described in detail below.

In some embodiments, the shell component can impart other propertiesrelating to robustness, such as being sufficient resistant to sustainmechanical forces or constraints in connection with swelling of the corepolymer and/or in connection with formulation (e.g., compressionencountered during tablet formulation).

In embodiments of the invention, the shell component can protect thecore component from the external environment such as thegastrointestinal tract. For example, the shell component can protectfunctional groups (e.g., acid groups) of the core components (e.g., of acore polymer) and prevent exposure thereof to the gastrointestinalenvironment.

In other embodiments, the core-shell component can comprise the corecomponent, the shell component (for example, comprising crosslinkedpolyvinylic polymer as described above)), and one or more further shellcomponents overlying the crosslinked polyvinylic polymer. For example,such further shell components can comprise an enteric coating, forexample an acid-insoluble polymer which prevents contact between apharmaceutical substance and the acidic contents of the stomach, butdisintegrates in the rising pH of the small intestine or colon andallows the pharmaceutical substance to be released. Suitable examples ofenteric coatings are described in the art. For example, see Remington:The Science and Practice of Pharmacy by A. R. Gennaro (Editor), 20^(th)Edition, 2000.

Non Absorbed

Preferably core-shell particles and the compositions comprising suchcore-shell particles are not absorbed from the gastro-intestinal tract.The term “non-absorbed” and its grammatical equivalents is not intendedto mean that the entire amount of administered polymer is not absorbed.It is expected that certain amounts of the polymer may be absorbed.

It is preferred that (about) 90% or more of the polymer is not absorbed,preferably (about) 95% or more is not absorbed, even more preferably(about) 97% or more is not absorbed, and most preferably (about) 98% ormore of the polymer is not absorbed.

Counterions

The core-shell particles, and particularly, core polymers and/or shellpolymers of the core-shell particle can include one or more counterions.Core polymers having a capacity for binding inorganic monovalent ionscan preferably comprise one or more cationic counterions. The cationscan be metallic, non-metallic, or a combination thereof. Examples ofmetallic ions include, but are not limited to, Ca²⁺-form, H⁺-form, NH₄⁺-form, Na⁺-form, or a combination thereof. Examples of non-metallicions include, but are not limited to, alkylammonium,hydroxyalkylammonium, choline, taurine, carnitine, guanidine, creatine,adenine, and aminoacids or derivatives thereof.

Shell Amount or Thickness/Core-Shell Particle Size

The size of the core-shell particles is not narrowly critical, and canbe adapted for a particular environment of interest and/or for aparticular application of interest. In particular, the amount of a shellcomponent and/or a thickness of a shell component can be controlledand/or optimized with respect to various characteristics and featuresdescribed herein, such as specific binding capacity, selectivity,persistence, robustness, etc., in each case, based for example on theguidance provided herein.

Generally, for example, the size of the core-shell particles cantypically range from (about) 100 nm to (about) 5 mm, and preferably from(about) 200 nm to (about) 2 mm, or from (about) 500 nm to (about) 1 mm,or from (about) 1 micron to (about) 500 microns. In some embodiments,the size of the core-shell particles are more than (about) 1 microns,more preferred is more than (about) 10 microns, even more preferred ismore than (about) 20 microns, and most preferred is more than (about) 40microns. In some embodiments, the size of the core-shell particles areless than (about) 250 microns, more preferred is less than (about) 150microns. In some embodiments, a particularly preferred size is (about)100 microns. In some embodiments, particularly preferred size is lessthan (about) 100 microns, and most preferred is less than (about) 50microns.

The particle size distribution is not narrowly critical. A relativelynarrow particle size distribution can result particles havingsubstantially similar kinetic behavior, with regard to the time forexchange of monovalent cations and the time for exchange of divalentcations. Generally, the particle size distribution can be controlledwith respect to kinetics of ion exchange for achieving a desired ionexchange kinetic profile, or with respect to compactibility or bulkdensity, or other properties of interest for formulation or use. Theparticle size distribution may be monomodal or multimodal (e.g.,comprising a mixture of two or more populations of particles, eachpopulation having a well defined and relatively narrow particle sizedistribution).

The particle shape is likewise not narrowly critical, but can bemeaningful in certain embodiments. In one embodiment, for example, fordelivery as an oral suspension, the particles can be spherical (e.g. fora reduced perception of roughness or grittiness in the mouth and throat)and the particles can be (about)<200 um in diameter, preferably lessthan <100 um, and still preferably less than 75, 60, 50, or 40 um. Inanother embodiment, for example, for a tablet (e.g., a swallowabletablet) or capsule formulation, the particles can have a nonsphericalshape and can be irregularly shaped particles, preferably with arelatively broad size distribution, allowing for improvedcompactibility, higher density, and improved tablet strength.

The amount of shell component, and/or a thickness of a shell componentover a surface of the core component is not narrowly critical, and canbe adapted for a particular environment of interest and/or for aparticular application of interest. In particular, the amount of a shellcomponent and/or a thickness of a shell component can be controlledand/or optimized with respect to various characteristics and featuresdescribed herein, such as specific binding capacity, selectivity,persistence, robustness, etc., in each case, based for example on theguidance provided herein.

The core-shell particle can preferably comprise a shell component and acore component in a relative amount generally ranging from (about)1:1000 to (about) 1:2 by weight. In preferred embodiments, the relativeamount of shell component to core component can range from (about) 1:500to (about) 1:4 by weight, or ranging from (about) 1:100 to (about) 1:5by weight, or ranging from (about) 1:50 to (about) 1:10 by weight.

In some embodiments, the shell component can have a thickness rangingfrom (about) 0.002 micron to (about) 50 micron, preferably (about) 0.005micron to (about) 20 microns, or from (about) 0.01 microns to (about) 10microns. In some embodiments, the shell thickness can be more than(about) 0.5 micron, preferably more than (about) 2 micron, or more than(about) 5 micron. In some embodiments, the shell thickness can be lessthan (about) 30 micron, preferably less than (about) 20 micron, or lessthan (about) 10 micron, or less than (about) 5 micron.

In Vitro Assays

The core-shell particles and the compositions of the invention arecharacterized with respect to various features, such as the extent ofbinding for a particular cation (e.g., potassium ion or sodium ion),selectivity, and/or persistence. Preferably, such characteristicfeatures of the compositions (or core-shell particles) are determinedunder a specified set of conditions.

In some cases, such characteristic features of the compositions (orcore-shell particles) can be determined using in vitro assay protocolsthat mimic or are representative of inorganic ion concentrations typicalof the gastrointestinal tract, and especially of the lower intestineand/or of the colon. Additionally, the assays may include componentswhich model other species (than inorganic ions) which are commonly foundin the gastrointestinal tract. Preferably, such characteristics aredetermined using an in vitro assay selected from GI Assay No. I, GIAssay No. II, GI Assay No. III, and combinations thereof (i.e.,combinations of two or more thereof) defined as follows.

A first assay, referred to herein as GI Assay No. I, is a relativelysimple competitive assay involving potassium ion and magnesium ion atequal molar concentrations selected to be generally typical andrepresentative of the concentrations seen in various regions of theintestinal tract, with the concentration of magnesium ion beingsufficiently high to be present in excess during the assay (e.g., toavoid substantial depletion of magnesium ion during the assay). Thisfirst assay consists essentially of incubating the composition (or thecore-shell particle) at a concentration of 4 mg/ml in a first assaysolution. The first assay solution comprises, and preferably consistsessentially of 55 mM KCl, 55 mM MgCl₂ and a buffer, 50 mM2-morpholinoethanesulfonic acid monohydrate, at a pH of 6.5 and atemperature of 37° C. The composition is incubated for 48 hrs withagitation. The cations bound to the composition are measured, directlyor indirectly, over time (e.g., as described below).

A second assay, referred to herein as GI Assay No. II, is a relativelysophisticated competitive assay involving potassium ion and magnesiumion and certain anions (e.g., including anions encountered in the uppergastrointestinal environment) that might modulate the performance of theshell material. This second assay consists essentially of incubating thecomposition (or core-shell particles) at a concentration of 4 mg/ml in asecond assay solution. The second assay solution can comprise andpreferably consists essentially of 50 mM KCl, 50 mM MgCl₂, 5 mM sodiumtaurocholate, 30 mM oleate, 1.5 mM citrate, and a buffer, 50 mM2-morpholinoethanesulfonic acid monohydrate. The composition isincubated at a pH of 6.5 and a temperature of 37° C. for 48 hrs withagitation. The cations bound to the composition are measured, directlyor indirectly, over time (e.g., as described below).

A third assay, referred to herein as GI Assay No. III, is an ex vivoassay involving ions present in human fecal water extracts, generallyrepresentative of the ion content and concentrations seen in the lowercolon. This third (fecal water) assay consists essentially of incubatingthe composition (or core-shell particles) at a concentration of 4 mg/mlin a fecal water solution. The fecal water solution is a filteredcentrifugal supernatant derived by centrifuging human feces for 16 hoursat 50,000 g at 4° C. and then filtering the supernatant through a 0.2 umfilter. The composition is incubated in the fecal water solution at atemperature of 37° C. for 48 hrs with agitation. The cations bound tothe composition are measured, directly or indirectly, over time (e.g.,as described below).

In each of the aforementioned assay protocols, GI Assay No. I, GI AssayNo. II, and GI Assay No. III, direct measurement of bound cations can beperformed by recovering the composition (core-shell particles) andanalyzing the ion content thereof, for example, by releasing boundcations by treating with acid or base, and measuring the releasedcations. In each of the described protocols, indirect measurement ofbound cations can be performed by determining the change in ionconcentration of the assay solution in the presence and absence of thecore-shell particles or composition being evaluated.

Each of these assay protocols (i.e., GI Assay No. I, GI Assay No. II,and GI Assay No. III) describe incubation of the composition (orcore-shell particles) at a concentration of 4 mg/mL in assay solutionscontaining various ions. The concentration of such composition (or thecore-shell particles) is not narrowly critical, however, and theseassays can alternatively be performed using other concentrations, takinginto account, for example, (1) the binding capacity of the core-shellparticles assayed, (2) the anticipated dose to be administered, (3) thedesired signal-to-noise ratio (which tends to increase with increasingcore-shell particle concentration), and (4) the concentration of thetarget ion within the contents at various locations of thegastrointestinal tract, which for potassium ion tends to increase as afunction of distance transited through the gastrointestinal tract (i.e.,from the stomach to the jejunum, ileum and then to the colon). Suchalternative concentrations may, for example, range from (about) 2 mg/mLto (about) 50 mg/mL in the assay solution. In various embodiments of theassay, the core-shell particle concentration can be 10 mg/mL, 20 mg/mL,or 40 mg/mL. Assays having protocols including these alternativecore-shell particle concentrations can be used with any of theembodiments of the invention described herein.

Determining Permeability

Methods for determining permeability coefficients are known. Forexample, see, W. Jost, Diffusion in Solids, Liquids and Gases, Acad.Press, New-York, 1960). For example, the ion permeability coefficient ina shell polymer can be measured by casting the polymer as a membraneover a solid porous material, subsequently contacted with aphysiological solution (donor) containing the ions of interest, andmeasuring steady state permeation rates of said ions, across themembrane in the acceptor solution. Membrane characteristics can then beoptimized to achieve the best cooperation in terms of selectivity andpermeation rate kinetics. Structural characteristics of the membrane canbe varied by modifying, for example, the polymer volume fraction (in theswollen membrane), the chemical nature of the polymer(s) and itsproperties (hydrophobicity, crosslinking density, charge density), thepolymer blend composition (if more than one polymer is used), theformulation with additives such as wetting agents, plasticizers, and/orthe manufacturing process.

Tuning of Permselctivity/Persistence

As discussed above, permselectivity and/or persistence of shell polymersfor inorganic monovalent ion over inorganic divalent ion can generallybe engineered and optimized (i.e., tuned) for an environment ofinterest. In particular, the shell component can be adapted to have areduced permeability for higher valency cations (divalent cations suchas magnesium ion and calcium ion) compared to permeability formonovalent cations, for an environment in which the core-shell particleswill be applied. Mg⁺⁺ and Ca⁺⁺ hydrated ions have a large size comparedwith monovalent cations such as K⁺ and Na⁺ as indicated below in Table 2(Nightingale E. R., J. Phys. Chem., 63, (1959), 1381-89).

TABLE 2 Metal ions Hydrated radii (angstroms) K⁺ 3.31 NH₄ ⁺ 3.31 Na⁺3.58 Mg⁺⁺ 4.28 Ca²⁺ 4.12

The differences in size and electronic properties of inorganic cationscan be the basis for differences in permeability that allow fordiscriminating between such cations in an environment of interest, andfor a period of interest. Generally, the permeability of the shellpolymer to alkaline-earth cations can be altered by changing the averagepore size, charge density and hydrophobicity of the membrane.

Some approaches for effecting reduced permeabilities to divalent cationsare generally known in the art, including for example from previousstudies on cation-exchange membranes for electrodialysis (e.g. Sata etal, J.Membrane Science, 206 (2002), 31-60). Disclosed methods areusually based on pore size exclusion and electrostatic interaction andcombination thereof.

When the mesh size of the shell material is in the same size range asthe solute dimensions, the diffusion of a bulkier divalent cationthrough the shell component can be significantly slowed down. Forexample, experimental studies (Krajewska, B., Reactive and Functionalpolymers 47, 2001, 37-47) report permeation coefficients in celluloseester or crosslinked chitosan gel membranes for both ionic and non-ionicsolutes. These studies show a lower permeation rate for bulkier soluteswhen membrane mesh size nears solute dimensions. The polymer volumefraction in a swollen (e.g., hydrated) resin is a good indicator of themesh size within the composition; theoretical studies have shown, forexample, that mesh size usually scales with φ^(−3/4), where φ is thepolymer volume fraction in the shell component swollen in a solution.The membrane swelling ratio, in turn, depends on factors which includethe hydrophobicity, crosslinking density, charge density, and solventionic strength.

Among approaches for tuning permeability, differentiation based onelectronic properties of the target monovalent ions and the competingdivalent ions can include a shell polymer that comprises or consistsessentially of a cationic polyelectrolyte. For example, a thin layer ofa cationic polyelectrolyte can be physically adsorbed to create a strongelectrical field that repels more highly charged cations such as Mg⁺⁺and Ca⁺⁺ (while having less repulsion effect on less charged cationssuch as K⁺ and Na⁺. Preferred cationic polyelectrolytes includehomopolymers or copolymers having a vinylic repeat unit such asvinylamine repeat unit. Other suitable cationic polyelectrolytes, forexample that can be used in combination with the preferred cationicpolyelectrolytes include but are not limited to, homopolymers orcopolymers with a repeat unit selected from ethyleneimine,propyleneimine, allylamine, vinylpyridines,alkyaminoalkyl(meth)acrylates, alkyaminoalkyl(meth)acrylamides,aminomethylstyrene, chitosan, adducts of aliphatic amine or aromaticamine with electrophiles (e.g., such as epichlorhydrin, alkylhalides orepoxydes) and wherein the amine is optionally a quaternized form.Adducts of aliphatic amine or aromatic amine with alkyldihalides arealso referred to as ionenes.

In another approach, the permselectivity of the core-shell particle canalso be controlled by pH, for example by varying the pH (or by takingadvantage of a pH variation in an environment of interest) to realize acorresponding change in core polymer charge density or shell polymercharge density, and/or to realize a corresponding change in the swellingratio of the core polymer or the shell polymer with the rate or extentof protonation or deprotonation. In particular, core polymers or shellpolymers can have ion exchange properties that vary with the local pH ofthe environment. For example, core particles comprising core polymerscan have a relative low binding capacity at gastric pH (e.g., as low as2 to 3) and have a relatively high binding capacity at pH greater than(about) 5.5. In one preferred embodiment, the core polymers of theinvention can have a fraction of capacity available at pH lower than(about) 3, (e.g., (about) 0-10% of the full capacity to the extentaffected by pH (i.e. measured at pH (about) 12)). The fraction ofcapacity available can be larger, for example greater than (about) 50%of the full capacity, at pH greater than (about) 4, and preferablygreater than (about) 5 or greater than (about) 5.5.

Some systems for core-shell particles can combine positive charges andhydrophobicity. For example, preferred shell polymers can include aminefunctional polymers, such as those disclosed above, which are optionallyalkylated with hydrophobic agents. In some cases, the alkylating agentscan comprise two or more amine-reactive moieties, and operate as acrosslinking alkylating agent. In some cases, alkylating agents can beintroduced through crosslinking reaction with hydrophobic crosslinkingagent, such as diglycidyl aniline.

Alkylation involves reaction between the nitrogen atoms of the polymerand the alkylating agent (usually an alkyl, alkylaryl group carrying anamine-reactive electrophile).

Preferred alkylating agents are electrophiles such as compounds bearingfunctional groups such as halides, epoxides, esters, anhydrides,isocyanate, or α,β-unsaturated carbonyls. They have the formula RX whereR is a C₁-C₂₀ alkyl (preferably C₄-C₂₀), C₁-C₂₀ hydroxy-alkyl(preferably C₄-C₂₀ hydroxyalkyl), C₆-C₂₀ aralkyl, C₁-C₂₀ alkylammonium(preferably C₄-C₂₀ alkyl ammonium), or C₁-C₂₀ alkylamido (preferablyC₄-C₂₀ alkyl amido) group and X includes one or more electrophilicgroups. By “electrophilic group” it is meant a group which is displacedor reacted by a nitrogen atom in the polymer during the alkylationreaction. Examples of preferred electrophilic groups, X, include halide,epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups,the alkylation reaction causes opening of the three-membered epoxy ring.

Examples of preferred alkylating agents include a C₃-C₂₀ alkyl halide(e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decylhalide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, andcombinations thereof); a C₁-C₂₀ hydroxyalkyl halide (e.g., an11-halo-1-undecanol); a C₁-C₂₀ aralkyl halide (e.g., a benzyl halide); aC₁-C₂₀ alkyl halide ammonium salt (e.g., a (4-halobutyl)trimethylammonium salt, (6-halohexyl)trimethyl-ammonium salt,(8-halooctyl)trimethylammonium salt, (10-halodecyl)trimethylammoniumsalt, (12-halododecyl)-trimethylammonium salts and combinationsthereof); a C₁-C₂₀ alkyl epoxy ammonium salt (e.g., a(glycidylpropyl)-trimethylammonium salt); and a C₁-C₂₀ epoxy alkylamide(e.g., an N-(2,3-eoxypropane)butyramnide, N-(2,3-epoxypropane)hexanamide, and combinations thereof). Benzyle halide and dodecyl halideare more preferred.

The alkylation step on the polyamine shell precursor can be carried outin a separate reaction, prior to the application of the shell onto thecore beads. Alternatively, the alkylation can be done once the polyamineshell precursor is deposited onto the core beads. In the latter case,the alkylation is preferably performed with an alkylating agent thatincludes at least two electrophilic groups X so that the alkylation alsoinduces crosslinking within the shell layer. Preferred polyfunctionalalkylation agents include di-halo alkane, dihalo polyethylene glycol,and epichlorohydrine. Other crosslinkers containing acyl chlorides,isocyanate, thiocyanate, chlorosulfonyl, activated esters(N-hydroxysuccinimide), or carbodiimide intermediates, are alsosuitable.

Typically, the level of alkylation is adjusted depending upon the natureof the polyamine precursor and the size of the alkyl groups used onalkylation. One factor that can affect the desired level of alkylationincludes the insolubility of the shell polymer under conditions of thegastrointestinal tract. In particular, a low pH as prevalent in thestomach tends to solubilize alkylated polyamine polymers having a pH ofionization of (about) 5 and above. For solubility considerations, ahigher extent of alkylation and/or a higher chain length alkyl arepreferred. As an alternative, one may use an enteric coating to protectthe shell material against acidic pH. The enteric coating can bereleased when the core-shell particles are passed into the lowergastrointestinal tract, such as the intestine. Another factor that canaffect the desired extent of alkylation includes the desiredpermselectivity profile/persistence. For example, when the extent ofalkylation is low, the persistence of the permselectivity for competingions (e.g. Mg²⁺, Ca²⁺) can be relatively shorter, for example, shorterthan the typical residence time in the colon. Conversely when the extentof alkylation (or the weight fraction of hydrophobes) is high, then theshell polymer can become less permeable to inorganic cations, and canhave a longer persistence. If the extent of alkylation is too high, theshell polymer material can become almost impermeable to most inorganiccations (e.g., and thus, the rate of equilibration or of approachingequilibration for K⁺ can become undesirably long). Preferably, thedegree of alkylation can be tuned and selected by an iterative approachconsidering such factors, among others.

In another approach and embodiment for controlling permeability (and inturn, permselectivity and/or persistence), the interaction of thepositively charged shell with some of the hydrophobic anions present theGI can achieve a higher level of permeability and/or persistence (forexample, as characterized by an increase in t₂₀ or t₈₀ value for Mg²⁺and Ca²⁺). Such hydrophobic anions include bile acids, fatty acids andanionic protein digests. Alternatively, anionic surfactants can providethe same or similar benefit. In this embodiment, the core-shell particleis either administered as is (for example into a gastrointestinalenvironment in which such fatty acids or bile acids or salts thereof caninteract with the shell polymer in vivo), or alternatively, thecore-shell particle can be formulated with fatty acids or bile acidsalts or even synthetic anionic detergents such as, but not limited to,alkyl sulfate, alkyl sulfonate, and alkylaryl sulfonate.

In more detail, the shell polymer of a core-shell composition can have apermselectivity controlled at least in part by passive absorption whilepassing through the upper GI tract. Many components present in the GItract including components of the diet, metabolites, secretion, etc. aresusceptible to adsorb onto and within the shell in a quasi-irreversiblemanner and can strongly modify the permeability pattern of the shell.The vast majority of these soluble materials are negatively charged andshow various levels of hydrophobicity. Some of those species have atypical amphiphilic character, such as fatty acids, phospholipids, bilesalts and can behave as surfactants. Surfactants can adsorbnon-specifically to surfaces through hydrophobic interactions, ionicinteraction and combinations thereof. In this embodiment, thisphenomenon is used to change the permeability of the polymericcomposition upon the course of binding potassium ions. In one embodimentfatty acids can be used to modify the permeability of the shell and inanother embodiment bile acids can be used. Fatty acids and bile acidsboth form aggregates (micelles or vesicles) and can also form insolublecomplexes when mixed with positively charged polymers (see e.g. Kanekoet al, Macromolecular Rapid Communications (2003), 24(13), 789-792).Both fatty acids and bile acids exhibit similarities with syntheticanionic surfactants and numerous studies report the formation ofinsoluble complexes between anionic surfactants and cationically chargedpolymers (e.g. Chen, L. et al, Macromolecules (1998), 31(3), 787-794).In this embodiment, the shell material is selected from copolymerscontaining both hydrophobic and cationic groups, so that the shell formsa complex with anionically charged hydrophobes typically found in the GItract, such as bile acids, fatty acids, bilirubin and related compounds.Suitable compositions also include polymeric materials described as bileacids sequestering agents, such as those reported in U.S. Pat. Nos.5,607,669; 6,294,163; and 5,374,422; Figuly et al, Macromolecules, 1997,30, 6174-6184. The formation of the complex induces a shell membranecollapse which in turn can lower the diffusion of bulky divalentcations, while preferably leaving the permeation of potassium unchanged.

In yet another embodiment, the permeability of the shell polymer of acore-shell composition can be modulated by enzymatic activity in thegastro-intestinal tract. There are a number of secreted enzymes producedby common colonic microflora. For example Bacteroides, Prevotella,Porphyromonas, and Fusobacterium produce a variety of secreted enzymesincluding collagenase, neuraminidase, deoxyribonuclease [DNase],heparinase, and proteinases. In this embodiment, the shell comprises ahydrophobic backbone with pendant hydrophilic entities that are cleavedoff via an enzymatic reaction in the gut. As the enzymatic reactionproceeds, the polymer membrane becomes more and more hydrophobic, andturns from a high swollen state, high permeability rate material to afully collapsed low hydration membrane with minimal permeability tobulky hydrated cations such as Mg⁺⁺ and Ca⁺⁺. Hydrophilic entities canbe chosen from natural substrates of enzymes commonly secreted in the GItract. Such entities include amino acids, peptides, carbohydrates,esters, phosphate esters, oxyphosphate monoesters, O- andS-phosphorothioates, phosphoramidates, thiophosphate, azo groups and thelike. Examples of enteric enzymes susceptible to chemically alter theshell polymer include, but are not limited to, lipases, phospholipases,carboxylesterase, glycosidases, azoreductases, phosphatases, amidasesand proteases. The shell can be permeable to potassium ions until itenters the proximal colon and then the enzymes present in the proximalcolon can react chemically with the shell to reduce its permeability tothe divalent cations.

Generally, regardless of the particular approach(es) adopted forcontrolling or tuning the permselectivity and/or persistence of thecore-shell particle, the permselective shell polymer membranes of theinvention can be optimized by studying their permselectivity profile asa function of polymer compositions and physical characteristics.

Permselectivity is preferably measured in conditions close to thoseprevailing in the milieu of use (e.g. colon). In a typical experiment,the donor solution is a synthetic fluid with an ionic composition,osmolality, and pH mimicking the colonic fluid, or alternatively, ananimal fluid collected through ileostomy or coleostomy, or by extractionof fluid from a tube which is threaded into the GI tract from the mouthor anus. In another embodiment, the membrane is sequentially contactedwith fluids that model the conditions found in the different parts ofthe GI tract, i.e. stomach, duodenum, jejunum, and ileum. In yet anotherembodiment, the shell is deposited on a cation exchange resin bead underthe proton form by microencapsulation method and contacted with a sodiumhydroxide aqueous solution. By monitoring pH or conductivity the rate ofpermeation of NaOH across the membrane is then computed. In anotherembodiment, the resin is preloaded with lithium cations and the releaseof lithium and absorption of sodium, potassium, magnesium, calcium andammonium are monitored by ion chromatography. Some preferred in vitroassays that can be used in connection with measuring permselectivity,for example, for purposes of tuning a core-shell particle in thatregard, include GI Assay No. I, GI Assay No. II, GI Assay No. III, andcombinations thereof, in each case as described in detail above.

Shell Polymers—Other Embodiments

Although the shell polymer preferably comprises a crosslinked polymer(i.e., homopolymer or copolymer), such as a crosslinked hydrophilicpolymer, or a crosslinked polyvinylic polymer, in some embodiments ofthe invention the shell polymer can more generally comprise polymers(i.e., homopolymers or copolymers) of other monomer repeat units, andcan more generally be crosslinked or non-crosslinked polymers. The shellpolymer can form a crosslinked gel with a three-dimensional networkstructure where chains are crosslinked through covalent bonds, ionic orother bonds (e.g., hydrogen bonds, or hydrophobic interactions).Preferably, polymer molecules (polymer chains) are crosslinked throughcovalent bonds. Generally, the shell polymer can be a film-formingpolymer. A shell polymer of the invention can generally comprise anatural or a synthetic polymer.

In some embodiments, the shell polymer can generally comprise an aminefunctional polymer (a polymer having repeat units comprising one or moreamine functional groups). Generally, amine functional groups canoptionally be in quaternized form. The amine functional polymers canoptionally be alkylated with one or more hydrophobic agents, details ofwhich (e.g., preferred alkylating agents, alkylation protocols, extentof alkylation, etc.) are described above in connection withcontrolling/tuning permselectivity and persistence, and can be likewiseapplied in connection herewith.

In some embodiments, the shell polymer can have a repeat unit(s)selected, for example, from one or more of ethyleneimine,propyleneimine, allylamine, vinylpyridines,alkyaminoalkyl(meth)acrylates, alkyaminoalkyl(meth)acrylamides,aminomethylstyrene, chitosan, adducts of aliphatic amine or aromaticamine with electrophiles (e.g., such as epichlorhydrine, alkylhalides orepoxydes) an ionenes.

In some embodiments, the shell polymer can comprise a polyvicinalamine.

In some embodiments, the shell polymer can comprise a polymer having arepeat units comprising one or more charged moieties, and in some cases,preferably one or more charged moieties other than a (protonated) aminemoiety. For example, the shell polymer can comprise a polymer having arepeat units comprising one more sulfonium moieties.

In some embodiments, the shell polymer can comprise repeat units havinghydrophobic groups or moieties. For example, the shell polymer cancomprise repeat units of hydrophobic monomers (e.g. long chain alcohol(meth)arylates, N-alkyl (meth)acrylamide).

In some embodiments, the shell polymer can have repeat units havinggroups or moieties that ionize subject to pH change. For example, theshell polymer can comprise repeat units of basic monomers. In someembodiments, such basic monomers can ionize at low pH and remain neutralbeyond their pKa (e.g. vinyl-pyridine, dialkylaminoethyl(meth)acrylamide).

In some embodiments, shell polymers can comprise repeat units includingeach of hydrophobic monomers and acidic monomers. In some embodiments,relative amounts of hydrophobic monomers and acidic monomers can bebalanced. For example, relative ratios of hydrophobic monomers to acidicmonomers can range, for example, from (about) 1:2 to (about) 2:1, andpreferably from (about) 2:3 to (about) 3:2. Such systems are extensivelydescribed in the literature. For example, see Kraft et al. Langmuir,2003, 19, 910-915; Ito et al, Macromolecule, (1992), 25, 7313-7316. Therelative amount hydrophobic monomers and acidic monomers can becontrolled to obtain physical characteristics and performancecharacteristics as described above (for example, in connection withrobustness and/or controlling/tuning of permselectivity andpersistence).

In other embodiments, the shell material can be chemically identical tothe core polymer of the core component, but with increasing crosslinkdensity as considered outward from core component to shell component.

In some embodiments, the shell component can be a shell polymer in abrush configuration—rather than a film forming polymer. Such polymerbrush shells components can comprise individual polymer strandscovalently attached to the core component at termini of the polymerstrands. In such embodiments, mesh size can be dictated by the densityof chains anchored onto the surface of the core component, and bymolecular weight of the polymer strands of the shell component. Polymerbrush design variables controlling permeability of polymer brush shellcomponents to solutes of various sizes and/or weights are known in theart. For example, see WO 0102452 (and references therein).

Generally, the shell component can comprise a crosslinked polymer,including crosslinked polymers of the various embodiments of the shellas described herein. The crosslinking agents can generally be the sameas those described above in connection with polyvinylic polymers such aspolyvinylamine polymers.

Generally, the various embodiments of shell polymers as described hereinare examples, and non-limiting. Generally, the various embodiments ofshell polymers as described herein can be used in various permutationsand combinations with each other. Generally, the shell polymers can beselected and optimized from among the various embodiments of shellpolymers as described herein and from other polymers known in the art,in each case to obtain physical characteristics and performancecharacteristics as described above (for example, in connection withrobustness and/or controlling/tuning of permselectivity and persistence)for a core-shell composite such as a core-shell particle.

Core Polymers—Other Embodiments.

The polymeric core can alternatively comprise other monovalention-binding polymers. In some embodiments, the monovalent-ion-bindingpolymers comprise acid groups in their protonated or ionized form, suchas sulfonic (—SO₃ ⁻), sulfuric (—OSO₃ ⁻), carboxylic (—CO₂ ⁻),phosphonic (—PO₃ ⁻⁻), phosphoric (—(OPO₃ ⁻⁻), or sulfamate (—NHSO₃ ⁻).Preferably, the fraction of ionization of the acid groups is greaterthan (about) 75% at the physiological pH in the colon and the potassiumbinding capacity is greater than (about) 5 mmol/gm. Preferably theionization of the acid groups is greater than (about) 80%, morepreferably it is greater than (about) 90%, and most preferably it is(about) 100%. In certain embodiments the acid containing polymerscontain more than one type of acid groups. In certain embodiments theacid containing polymers are administered in their anhydride form andgenerate the ionized form when contacted with physiological fluids.

In some other embodiments, a pK_(a)-decreasing group, preferably anelectron-withdrawing substituent, is located adjacent to the acid group,preferably it is located in the alpha or beta position of the acidgroup. The preferred electron-withdrawing substituents are a hydroxylgroup, an ether group, an ester group, or an halide atom, and mostpreferably F. Preferred acid groups are sulfonic (—SO₃ ⁻), sulfuric(—OSO₃ ⁻), carboxylic (—CO₂ ⁻), phosphonic (—PO₃ ⁻⁻), phosphoric (—(OPO₃⁻⁻), or sulfamate (—NHSO₃ ⁻). Other preferred polymers result from thepolymerization of alpha-fluoro acrylic acid, difluoromaleic acid, or ananhydride thereof.

Examples of other suitable monomers for monovalent-ion-binding polymersfor core polymers are disclosed in the related application U.S.application Ser. No. 11/096,209 filed Mar. 30, 2005, incorporated hereinby reference in this regard. For example, some of such core polymershave repeat units disclosed in Table 3.

TABLE 3 Fraction of Fraction of Expected Molar mass per Theoreticaltitrable H titrable H Capacity Expected Capacity charge capacity @ pH 3@ pH 6 @ pH3 @ pH6

71  14.1  0.05  .35  0.70  4.93

87  11.49 0.2  0.95 2.3 10.92

53  18.9  0.25 0.5   4.72  9.43

 47.5 21.1  0.25 0.5   5.26 10.53

57  17.5  0.1  0.5   1.75  8.77

107   9.3 1   1    9.35  9.35

93  10.8  1   1   10.75 10.75

63  15.9  0   0.4  0    6.35

125   8   1   1   8   8  

183   5.5 1   1    5.46  5.46

87  11.49 .1 .6  1.14  6.89

The core polymer can alternative by selected from other suitable cationexchange polymers, including for example:

wherein n is equal to or greater than one and Z represents either SO₃Hor PO₃H. Preferably n is (about) 50 or more, more preferably n is(about) 100 or more, even more preferred is n (about) 200 or more, andmost preferred is n (about) 500 or more.

Core polymers can comprise repeat units of suitable phosphonate monomersincluding vinyl phosphonate, vinyl 1,1 bis phosphonate, and ethylenicderivatives of phosphonocarboxylate esters,oligo(methylenephosphonates), and hydroxyethane-1,1-diphosphonic acid.Methods of synthesis of these monomers are well known in the art.

Core polymers can also comprise sulfamic (i.e. when Z═SO₃H) orphosphoramidic (i.e. when Z═PO₃H) polymers. Such polymers can beobtained from amine polymers or monomer precursors treated with asulfonating agent such as sulfur trioxide/amine adducts or aphosphonating agent such as P₂O₅, respectively. Typically, the acidicprotons of phosphonic groups are exchangeable with cations, like sodiumor potassium, at pH of (about) 6 to (about) 7.

Core polymers can comprise free radical polymers derived from monomerssuch as vinyl sulfonate, vinylphosphonate, or vinylsulfamate.

The core polymers of the invention can also include cation exchangeresins comprising from naturally occurring polymers, such as saccharidepolymers and semi-synthetic polymers, optionally functionalized tocreate ion exchange sites on the backbone or on the pendant residues.Examples of polysaccharides of interest include materials from vegetalor animal origins, such as cellulosic materials, hemicellulose, alkylcellulose, hydroxyalkyl cellulose, carboxymethylcellulose,sulfoethylcellulose, starch, xylan, amylopectine, chondroitin,hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin andchitosan. Most preferred are polymers that do not degrade under thephysiological conditions of the gastrointestinal tract and remainnon-absorbed, such as carboxymethylcellulose, chitosan, andsulfoethylcellulose.

Generally, the core component comprising core polymers can be formed bypolymerization processes using either homogeneous or heterogeneous mode:in the former case a crosslinked gel is obtained by reacting the solublepolymer chains with a crosslinker, forming a bulk gel which is eitherextruded and micronized, or comminuted to smaller sized particles. Inthe former case, the particles are obtained by emulsification ordispersion of a soluble polymer precursor, and subsequently crosslinked.In another method, the particles are prepared by polymerization of amonomer in an emulsion, suspension, miniemulsion or dispersion process.The continuous phase is either an aqueous vehicle or an organic solvent.When a suspension process is used, any suitable type of variants ispossible, including methods such as “templated polymerization,”“multistage′seeded suspension,” all of which yielding mostlymonodisperse particles. In one particular embodiment, the beads areformed using a “jetting” process (see U.S. Pat. No. 4,427,794), wherebya “tube of liquid containing a monomer plus initiator mixture is forcedthrough a vibrating nozzle into a continuous phase. The nozzles can bearranged in spinning turret so as to force the liquid under centrifugalforce.

Synthesis of Core-Shell Particles

The shell is component can be formed over a surface of the corecomponent. Preferably, the shell component can be formed over an entireexposed surface of a core component, especially in embodiments where thecore component comprises a particle. Preferably, the shell component canbe substantially uniformly formed (e.g., coated) over a surface of thecore component. In some embodiments, the shell component can have anessential absence of pinholes or substantial macroporosity.

Generally, the shell (or a shell precursor for a crosslinked shell) canbe formed by chemical or non-chemical processes. Non-chemical processesinclude spray coating, fluid bed coating, solvent coacervation inorganic solvent or supercritical CO₂, solvent evaporation, spray drying,spinning disc coating, extrusion (annular jet) or layer by layerformation. Examples of chemical processes include interfacialpolymerization, grafting from, grafting unto, and core-shellpolymerization.

Crosslinked shells can generally be formed by crosslinking a shellpolymer using a crosslinking agent under crosslinking conditions. Forexample, a (non-crosslinked) shell precursor can be formed as describedabove by a chemical or a non-chemical process, and crosslinked. Thecrosslinking can be a separate independent step (typically in aseparate, independent reaction zone), or can be integrated with achemical or non-chemical processes, for example as described above. Atypical process for forming a crosslinked shell polymer over a polymercore can include, for example, a layer-by-layer process in which acharged core material such as a cation-binding polymer (e.g., a cationexchange resin) is contacted with a shell polymer such as apolyelectrolyte of opposite charge to form a polymer complex. Thecontacting step can be repeated, optionally with intermittent dryingsteps, until a multilayer shell polymer is deposited on a core surface.The composite material comprising the multilayer shell polymer formedover the core is then physically isolated, optionally washed orotherwise worked up, and subsequently, crosslinked in a separateindependent step, and typically in an independent reaction zone.

Preferred Methods for Shell Preparation—Multiphase In-Situ Crosslinking

In a preferred process, a core-shell composite (such as a core-shellparticle) comprising a core component and a crosslinked shell polymerformed over a surface of the core component is prepared using amultiphase process with in situ crosslinking.

The preferred process can comprise, in a general first embodiment,forming a core-shell intermediate comprising a core component, and ashell polymer associated with a surface of the core component, thecore-shell intermediate being formed for example in a first liquidphase. The core-shell intermediate is phase-isolated from a bulk portionof the first liquid phase. Preferably, the core-shell intermediate isphase-isolated using a second liquid phase, the second liquid phasebeing substantially immiscible with the first liquid phase. Preferably,the second liquid phase can be a non-solvent for the shell polymer, suchthat the shell polymer remains substantially within the first liquidphase comprising the core-shell intermediate. The phase-isolatedcore-shell intermediate is contacted with a crosslinking agent undercrosslinking conditions (to crosslink the shell polymer associated withthe surface of the core component). The resulting product is thecore-shell composite comprising a cross-linked shell polymer over asurface of a core component.

In one preferred second embodiment, the core component can be apolymeric core component comprising a core polymer, and preferably ahydrophilic polymer. The first liquid phase can be a first aqueous phasecomprising an aqueous solution. The core component can be hydrated inthe first aqueous phase. Shell polymer, preferably a hydrophilic shellpolymer, can be dissolved or substantially dissolved in the aqueoussolution. The shell polymer can be allowed to interact with a surface ofthe hydrated core component to form a hydrated core-shell intermediatein the first aqueous phase. The hydrated core-shell intermediate can bephase-isolated from a bulk portion of the first aqueous phase.Preferably, the hydrated core-shell intermediate is phase-isolated usinga second liquid phase. Preferably, the second liquid phase issubstantially immiscible with the first aqueous phase. Preferably, thehydrophilic shell polymer is substantially insoluble in the secondliquid phase. Preferably, the second liquid phase can comprise acrosslinking agent. The phase-isolated, hydrated core-shell intermediateis contacted with a crosslinking agent under crosslinking conditions (tocrosslink the shell polymer interacting with the surface of the corecomponent) to form the core-shell composite.

In some embodiments, it can be advantageous to remove at least a portionof the first liquid phase media. For example, in embodiments in whichthe first liquid phase is a first aqueous phase, the first liquid phasemedia can be dehydrated. Without being bound by theory not specificallyrecited in the claims, such removal of first liquid phase media (e.g.,dehydration) can facilitate association of the shell polymer with asurface of the core component (e.g., can facilitate interaction of ashell polymer, such as a dissolved shell polymer, with a surface of thehydrated core component. Without being bound by theory not specificallyrecited in the claims, such removal of first phase liquid media (e.g.,dehydration) may also favorably affect phase isolation. The removal(e.g., dehydration) can occur before, during and/or after phaseisolation. Preferably, the removal (e.g., dehydration) is at leastconcurrent with shell-polymer association and/or interaction with corecomponent, and/or with phase isolation and/or with the crosslinkingreaction. Most preferably, the dehydration occurs after phase isolationand simultaneously with crosslinking, such that the shell componenthydrophilic polymer is restricted to occupy a decreasing volume as thecrosslinking progresses, resulting in a higher crosslink density and/orsmaller mesh size as a result of crosslinking in a less-swollen state.

Preferably, therefore, the various embodiments of the process forpreparing a core-shell composite (including but not limited to thegeneral first embodiment and the preferred second embodiment (asdescribed above) as well as further embodiments (as described below))can further comprise removing at least a portion of the first liquidphase (e.g., a portion of a first liquid of the first liquid phase). Inembodiments in which the first liquid phase is a first aqueous phase,the method can further comprise dehydrating to remove water.

In another general third embodiment, for example, a core-shell compositecomprising a polymeric core component and a crosslinked polymeric shellcomponent can be prepared as follows. A first phase is preparedcomprising a polymeric core component and a shell polymer in a firstliquid, the shell polymer being dissolved or substantially dissolved inthe first liquid. A second phase is prepared comprising a crosslinkingagent in a second liquid. The second liquid is substantially immisciblewith the first liquid. Preferably, the shell polymer is substantiallyinsoluble in the second liquid. The first phase and the second phase canbe combined to form a heterogeneous multiphase media. (Preferably,formation of the heterogeneous multiphase media phase-isolates acore-shell intermediate (comprising a core component and a shell polymerassociated with a surface of the core component)). At least a portion ofthe first liquid is removed from the heterogeneous multiphase media. Theshell polymer is crosslinked with the crosslinking agent (on a surfaceof the core component) to form the core-shell composite in themultiphase media.

In another preferred fourth embodiment, the core component can be apolymeric core component comprising a core polymer, and preferably ahydrophilic polymer. The first liquid phase can be a first aqueous phase(comprising an aqueous solution). The core component can be hydrated inthe first aqueous phase. Shell polymer, preferably a hydrophilic shellpolymer, can be dissolved or substantially dissolved in the firstaqueous phase (in the aqueous solution). The first aqueous can becombined and mixed with a second phase. The second phase can comprise acrosslinking agent. The second phase can preferably be substantiallyimmiscible with the first aqueous phase, such that combining and mixingforms a heterogeneous multiphase media. The shell polymer can preferablybe substantially insoluble in the second phase. The heterogeneousmultiphase media is preferably dehydrated. The shell polymer iscrosslinked with the crosslinking agent (on a surface of the corecomponent) to form the core-shell composite.

In another preferred fifth embodiment, the core-shell composite isformed without physically separating the hydrated core-shellintermediate from a bulk portion of the aqueous solution in the presenceof the aqueous solution. Briefly, the method can comprise hydrating acore component in an aqueous solution, the core component comprising a(hydrophilic) core polymer, dissolving a shell polymer in the aqueoussolution (where preferably the shell polymer is a hydrophilic shellpolymer), and allowing the shell polymer to interact with a surface ofthe hydrated core component to form a hydrated core-shell intermediatein the aqueous solution. Without physically separating the hydratedcore-shell intermediate from a bulk portion of the aqueous solution, thehydrated core-shell intermediate is contacted with a crosslinking agentunder crosslinking conditions to form the core-shell composite.

In further embodiments, the core-shell composite can be preparedadvantageously be effecting some steps concurrently with each other. Forexample, in a further set of embodiments, the method for preparing acore-shell composite can comprise hydrating a core component (preferablycomprising a hydrophilic core polymer) in an aqueous solution, anddissolving or substantially dissolving a shell polymer in the aqueoussolution. The shell polymer can preferably be a hydrophilic shellpolymer. The method can further comprise any two or all three of thefollowing steps (i), (ii) and/or (iii) being effected concurrently: (i)allowing the shell polymer to interact with a surface of the hydratedcore component to form a hydrated core-shell intermediate, (ii)contacting the hydrated core-shell intermediate with a crosslinkingagent under crosslinking conditions, such that a core-shell composite isformed, and (iii) removing water from the aqueous solution.Specifically, for example, further sixth embodiment comprisesconcurrently (i) allowing the shell polymer (preferably a hydrophilicpolymer, and preferably dissolved or substantially dissolved in anaqueous solution) to interact with a surface of the hydrated corecomponent to form a hydrated core-shell intermediate, and (ii)contacting the hydrated core-shell intermediate with a crosslinkingagent under crosslinking conditions, such that a core-shell composite isformed. A further seventh embodiment can comprise concurrently (i)contacting the hydrated core-shell intermediate (formed by allowing ashell polymer (preferably a hydrophilic polymer, and preferablydissolved or substantially dissolved in an aqueous solution) to interactwith a surface of a hydrated core component) with a crosslinking agentunder crosslinking conditions, such that a core-shell composite isformed, and (ii) removing water from the aqueous solution. A furthereight embodiment can comprise concurrently effecting each of (i)allowing the shell polymer (preferably a hydrophilic polymer, andpreferably dissolved or substantially dissolved in an aqueous solution)to interact with a surface of the hydrated core component to form ahydrated core-shell intermediate, (ii) contacting the hydratedcore-shell intermediate with a crosslinking agent under crosslinkingconditions, such that a core-shell composite is formed, and (iii)removing water from the aqueous solution.

Preferably, in a preferred ninth embodiment, the core-shell compositecan be prepared advantageously by forming the core-shell compositewithout substantially forming crosslinked shell polymer aggregates in abulk portion of the aqueous solution. Such method can further comprisehydrating a core component in an aqueous solution (e.g, the corecomponent comprising a hydrophilic core polymer), dissolving a shellpolymer in the aqueous solution (e.g., the shell polymer being ahydrophilic shell polymer), allowing the shell polymer to interact witha surface of the hydrated core component to form a hydrated core-shellintermediate, and contacting the hydrated core-shell intermediate with acrosslinking agent under crosslinking conditions, without forming thecrosslinked shell aggregates in a bulk portion of the aqueous solution.

Further details, features and characteristics of the methods aredescribed hereinafter that can be used in each permutation and variouscombination with the aforementioned general and preferred embodimentsand features described therein

Preferred shell polymers can be as described above (in connection withthe description for the core-shell particles).

Preferred core components can be inorganic or organic core components.Especially preferred core components are core polymers as describedabove (in connection with the description for the core-shell particles).

Preferred crosslinking agents can be as described above (in connectionwith the description for the core-shell particles). Preferably, themolar ratio of the feed (or amount) of crosslinking agent to shellpolymer (e.g., to repeat units of the shell polymer or to crosslinkablefunctional groups of the shell polymer) is not less than 1:1, andpreferably is not less than (about) 2:1, or not less than (about) 3:1,or not less than (about) 3.5:1 or not less than (about) 4:1. In someembodiments, the molar ratio of the feed (or amount) of crosslinkingagent to shell polymer (e.g., to repeat units of the shell polymer or tocross-linkable functional groups of the shell polymer) is even higher,including not less than (about) 4.5:1, or not less than (about) 5:1 ornot less than (about) 6:1. Without being bound by theory not recited inthe claims, a substantial excess of crosslinking agent can facilitatecontacting of the (hydrated) core-shell intermediate with thecrosslinking agent. The particular ratio/amount for a particular systemcan be determined, for example, as described above to obtain preferredphysical characteristics and/or performance characteristics, in eachcase as as described above (in connection with the description for thecore-shell particles).

The crosslinking conditions are not narrowly critical, and can generallybe determined based on the particular crosslinking agent employed, theshell polymer, and other factors well known in the art. Generally, thecrosslinking can be effected at a temperature sufficient to thermallyintitiate and/or sustain crosslinking of the shell polymer in themethod. For example, the temperature can be increased to initiatecrosslinking, for example, to a temperature ranging from (about) 70° C.to (about) 100° C. Alternatively, the temperature during the addition ofthe crosslinking reagent can be (about) 50° C. to (about) 90° C. Thereaction temperature can then possibly be adjusted to a temperatureranging from (about) 70° C. to (about) 120° C.; preferably from (about)85° C. to (about) 110° C. The reaction mixture is heated for (about) 1to about 12 hours at the temperature described above. The hightemperature may be constrained by considerations involving thevolatility of the liquid phases and/or the pressure of the system.

Preferably, liquid removal such as dehydration can be effected using oneor more unit operations known in the art. In a preferred approach, forexample, a liquid can be removed by distillation process, including forexample azeotropic distillation, to selectively remove a liquid of the(shell polymer containing) first phase without substantially removing aliquid of the (cross-linker containing) second phase.

Preferably, the multiphase media can be agitated (e.g., stirred) inconnection with any embodiment described herein, using equipment andprotocols known in the art. Without being bound by theory not recited inthe claims, and without limitation, such agitation can facilitatephase-isolation, and contacting of crosslinking agent with thecore-shell intermediate.

In any case, the multiphase in situ crosslinking method can furthercomprise one or more work-up steps, such as separating the formedcore-shell composite from the heterogenous, multiphase mixture, andpurifying, for example by washing in one or more solvents.

In a particularly preferred approach, a core-shell composite comprisinga polymeric core component and a crosslinked polymeric shell componentcan be prepared as follows. A first aqueous phase is prepared comprisinga polymeric core, such as polystyrenesulfonate core (e.g., commerciallyavailable as Dowex), and a polyvinylic shell polymer (e.g.,polyvinylamine) dissolved in a first aqueous solution. Separately, asecond phase is prepared comprising a crosslinking agent, preferably ahydrophobic crosslinking agent (e.g., N,N-diglycidylaniline) in a secondorganic phase, or preferably a crosslinking agent with preferentialpartition (e.g., epichlorohydrine, N,N-diglycidylaniline) in a secondorganic phase, in each case such as a second organic phase comprisingtoluene, xylene, etc.. The first phase and the second phase are combinedto form a heterogeneous multiphase media. Preferably, the heterogenousmixture is mixed, for example, by stirring, and crosslinking conditionsare initiated by raising the system temperature to (about) 85 C for(about) 2 hours. Following, the multiphase media is dehydrated to removewater, preferably for example using a Dean-Starke distillation at atemperature of (about) 110 C. The shell polymer is crosslinked with thecrosslinking agent (on a surface of the core component) to form thecore-shell composite in the multiphase media. The core-shell compositeis isolated, for example by decanting the liquid portion of themultiphase media. The core-shell composite is then washed, for example,in separate steps with methanol, and subsequently with water.

Such multiphase in situ crosslinking method offers substantialadvantages over convention processes. Generally, for example, the methodprovides for improved control over the amount and/or thickness and/oruniformity of the crosslinked shell polymer formed over a surface of thecore component. Notably, for example, as compared to layer-by-layerprocess involving separate steps of adsorption and subsequentcrosslinking, a greater amount/thickness of a shell polymer can beformed on a core component using the multiphase in situ crosslinkingmethod, as described herein. In some embodiments, the shell thicknessusing the method of the invention can be 10 times more, or 50 times moreor even 100 times more or even 500 times more than the thicknessachievable with such layer-by-layer process. Likewise, as compared torecirculated fluidized bed (Wurster) coating approaches, a smalleramount/thickness of a shell polymer can be formed (e.g., as a layer andpreferably as a uniform layer) on a core component using the multiphasein situ crosslinking method, as described herein. In some embodiments,the amount of shell material of the core-shell composite prepared usingthe method of the invention can be (about) 5% less, or (about) 10% lessor (about) 15% less than that achievable using typical recirculatedfluidized bed processes (based, in each case, by weight of shellcomponent relative to weight of the core component of the core-shellcomposite). Accordingly, the method provides a unique approach forpreparing core-shell composites having a different, and commerciallymeaningful amount/thickness of crosslinked shell polymer. In particular,the method can be used to prepare core-shell composite materials havinga shell thickness in the ranges as generally recited above, and inpreferred embodiments, for example, the method can prepare shellcomponents having a thickness ranging from (about) 0.002 micron to(about) 50 micron, preferably (about) 0.005 micron to (about) 20microns, or from (about) 0.01 microns to (about) 10 microns.Additionally, the multiphase in situ crosslinking method offers ascaleable, commercially reasonable approach for preparing suchcore-shell composites.

Other Methods for Shell Preparation

In fluid bed coating, typically the core beads are kept in arecirculating fluidized bed (Wurster type) and sprayed with a coatingsolution or suspension. The coating polymer can be used as a solution inalcohols, ethylacetate, ketones, or other suitable solvents or as latex.Conditions and formulations/compositions are typically optimized so asto form a tight and homogeneous membrane layer, and insure that nocracks are formed upon swelling when the particles are contacted withthe aqueous vehicle. It is preferred that the membrane polymer can yieldto the volume expansion and elongates so as to accommodate the dimensionchange. This can be aided by selecting a shell polymer composition whichswells to some extent upon contact with water, and becomes heavilyplasticized by the water. Polymer membranes have an elongation at breakgreater than 10%, preferably greater than 30%. Examples of this approachare reported in Ichekawa H. et al, International Journal ofPharmaceuticals, 216(2001), 67-76.

Solvent coacervation is described in the art. For example, see Leach, K.et al., J. Microencapsulation, 1999, 16(2), 153-167. In this process,typically two polymers, core polymer and shell polymer are dissolved ina solvent which is further emulsified as droplets in an aqueous phase.The droplet interior is typically a homogeneous binary polymer solution.The solvent is then slowly driven off by careful distillation. Thepolymer solution in each droplet undergoes a phase separation as thevolume fraction of polymer increases. One of the polymer migrates to thewater/droplet interface and forms a more- or less perfect core-shellparticle (or double-walled microsphere).

Solvent coacervation is another method that can be employed to deposit acontrolled film of shell polymer onto the core. In one embodiment, thecoacervation technique consists in dispersing the core beads in acontinuous liquid phase containing the shell material in a soluble form.The coacervation process then consists of gradually changing thesolvency of the continuous phase so that the shell material becomesincreasingly insoluble. At the onset of precipitation some of the shellmaterial ends up as a fine precipitate or film at the bead surface. Thechange in solvency can be triggered by a variety of physical chemistrymeans such as, but not limited to, changes in pH, ionic strength (i.e.osmolality), solvent composition (through addition of solvent ordistillation), temperature (e.g when a shell polymer with a LCST (lowercritical solution temperature) is used), pressure (particularly whensupercritical fluids are used). More preferred are solvent coacervationprocesses when the trigger is either pH or solvent composition.Typically when a pH trigger event is used and when the polymer isselected from an amine type material, the shell polymer is firstsolubilized at low pH. In a second step the pH is gradually increased toreach the insolubility limit and induce shell deposition; the pH changeis often produced by adding a base under strong agitation. Anotheralternative is to generate a base by thermal hydrolysis of a precursor(e.g. thermal treatment of urea to generate ammonia). The most preferredcoacervation process is when a ternary system is used comprising theshell material and a solvent/non-solvent mixture of the shell material.The core beads are dispersed in that homogeneous solution and thesolvent is gradually driven off by distillation. The extent of shellcoating can be controlled by on-line or off-line monitoring of the shellpolymer concentration in the continuous phase. In the most common casewhere some shell material precipitates out of the core surface either ina colloidal form or as discrete particle, the core-shell particles areconveniently isolated by simple filtration and sieving. The shellthickness is typically controlled by the initial core to shell weightratio as well as the extent of shell polymer coacervation describedearlier. The core-shell beads can then be annealed to improve theintegrity of the outer membrane as measured by competitive binding.

Supercritical CO₂ coating is described in the art. For example, seeBenoit J. P. et al, J. Microencapsulation, 2003, 20(1)87-128. Thisapproach is somewhat a variant of the solvent coacervation. First theshell coating material is dissolved in the supercritical CO₂, and thenthe active is dispersed in that fluid in super-critical conditions. Thereactor is cooled down to liquid CO₂ conditions wherein the shellmaterial is no longer soluble and precipitates on the core beads. Theprocess is exemplified with shell materials selected from smallmolecules such as waxes and paraffins. The core-shell material isrecovered as a powder.

The spinning disc coating technique is based on forming a suspension ofthe core particles in the coating, then using a rotating disc to removethe excess coating liquid in the form of small droplets, while aresidual coating remains around the core-particles. See U.S. Pat. No.4,675,140.

In the layer by layer process, a charged core material is contacted witha polyelectrolyte of opposite charge and a polymer complex is formed.This step is repeated until a multilayer is deposited on the coresurface. Further crosslinking of the layers are optional.

Interfacial polymerization consists of dispersing the core materialcontaining one reacting monomer in a continuous phase containing aco-reacting monomer. A polymerization reaction takes place at the coreinterface creating a shell polymer. The core can be hydrophilic orhydrophobic. Typical monomer used for that purpose can includediacylchlorides/diamines, diisocyanates/diamines, diisocyanates/diols,diacylchlorides/diols and bischloroformate and diamines or diols.Trifunctional monomers can also be used to control the degree ofporosity and toughness of the membranes.

In yet another embodiment, the shell is formed by contacting the ionexchange material with a polymer dispersion of opposite charge (i.e. thecore material is typically charged negatively and the shell positively),and filter the bead particles and anneal them in a fluidized bed at atemperature higher than the transition temperature (or softening point)of the shell polymer. In this embodiment the polymer dispersion is alatex or a polymer colloidal dispersion of particle size in the micronto sub-micron range.

In one further embodiment, the shell material comprises treating theacid containing core material or its derivatives such as methyl ester oracyl chloride with reactive monomer or polymer. Preferably the acidreactive material is a polymer and more preferably a polyamine: forinstance a carboxylated core polymer is treated with polyethyleneimineat high temperature in an organic solvent to create amide bonds betweenthe COOH groups and the NH and NH₂ groups. It can also be useful toactivate the acid functions to facilitate the amide bond formation, e.g.by treating COOH or SO₃H groups with thionylchloride or chlorosulfonicacid to convert said groups into their acid chloride forms. See Sata etal., Die Angewandte Makromolekulare Chemie 171, (1989) 101-117 (Nr2794).

The process of “grafting from” involves an active site capable ofinitiating polymerization on the core surface and polymer chains aregrown from the surface in monolayers. Living polymerization methods suchas nitroxide-mediated living polymerizations, ATRP, RAFT, ROMP are mostsuitable, but non living polymerizations have also been applied.

In the process of “grafting onto” a small molecule (typically anelectrophile, such as epoxy, isocyanate, anhydride, etc.) is brought incontact with the polymeric core material, said core carrying reactivespecies (typically nucleophile groups such as amine, alcohol, etc.). Thethickness of the shell thus formed is controlled by the rate ofdiffusion of the shell small molecule precursor and the rate of reactionwith the core. Slow-diffusing/highly reactive species tend to confinethe reaction within a short distance from the core surface thusproducing a thin shell. Whereas, fast-diffusing/slow reacting speciestend to invade the entire core with no defined shell and form a gradientrather than a sharp shell to core boundary.

Core-shell polymerizations can be emulsion polymerization,suspension/mini-emulsion polymerization, or dispersion polymerization.All these processes employ free radical polymerizations. In emulsionpolymerization, the polymerization takes place in aqueous medium with asurfactant, monomer with a low water solubility, and a water solublefree radical initiator. Polymer particles are formed by micellar orhomogeneous nucleation or both. Core shell particles can be formedtheoretically by feeding the core monomer first and the shell monomersecond as long as the monomer is spontaneously consumed as it is fed(“starved regime”). The potassium binding core beads are preferably madefrom a water insoluble monomer (e.g. alkylester of α-fluoro-acrylicacid).

In suspension/mini-emulsion polymerization, the free radical initiatoris soluble with the monomer. Monomer and initiator are pre-dissolved andthen emulsified in droplet stabilized with either surfactant oramphiphilic polymers. This method allows one pre-formed polymer (e.g.the shell polymer) to be dissolved as well. When the reaction proceeds,the shell polymer and the core polymer phase separate to form thedesired core-shell particles.

In dispersion polymerization, both the monomer and the initiator aresoluble in the continuous phase (usually an organic solvent). A blockcopolymer is used as a steric stabilizer. The polymer particles areformed by homogenous nucleation and subsequent growth. Particle size areon the 1 to 10 microns range and mono-dispersed.

In a preferred process of dispersion, polymerization employs arefinement reported in Stover H. et al, Macromolecules, 1999, 32,2838-2844, described thereafter: The shell monomer contains a largefraction of divinyl monomer, such as 1,4 divinylbenzene, while the coreparticles present some polymerizable double bond on their surface; theshell polymerization mechanism is based on the formation of shortoligoradicals in the continuous phase, which are captured by the doublebond present on the particle surface. The oligomers themselves containnon-reacted insaturation that replenish the surface in reactive doublebonds. The net result is a formation of a crosslinked shell with a sharpboundary with the shell and the core material.

In one embodiment, a core-shell composition of the invention issynthesized by forming the cation exchange core in a conventionalinverse suspension process using suitable monomers; decorating theparticle surface with reactive double bonds by post-reacting with theacidic group present on the particle core; and dispersing in typicaldispersion polymerization solvent such as acetonitrile (e.g. anon-solvent for the cation-exchange core polymer) and adding apolymerizing mixture of DVB or EGDMA with a functional monomers.

Use of Core-Shell Compositions/Methods of Treatment

The methods and compositions described herein are suitable for treatmentof hyperkalemia caused by disease and/or use of certain drugs.

In some embodiments of the invention, the compositions and methodsdescribed herein are used in the treatment of hyperkalemia caused bydecreased excretion of potassium, especially when intake is not reduced.A common cause of decreased renal potassium excretion is renal failure(especially with decreased glomerular filtration rate), often coupledwith the ingestion of drugs that interfere with potassium excretion,e.g., potassium-sparing diuretics, angiotensin-converting enzymeinhibitors (ACEIs), non-steroidal anti-inflammatory drugs, heparin, ortrimethoprim. Impaired responsiveness of the distal tubule toaldosterone, for example in type IV renal tubular acidosis observed withdiabetes mellitus as well as sickle cell disease and/or chronic partialurinary tract obstruction is another cause of reduced potassiumsecretion. Secretion is also inhibited in diffuse adrenocorticalinsufficiency or Addison's disease and selective hypoaldosteronism.Hyperkalemia is common when diabetics develop hypoteninemichypoaldosteronism or renal insufficiency (Mandal, A. K. 1997.Hypokalemia and hyperkalemia. Med Clin North Am. 81:611-39).

In certain preferred embodiments, the potassium binding polymersdescribed herein are administered chronically. Typically, such chronictreatments will enable patients to continue using drugs that causehyperkalemia, such as potassium-sparing diuretics, ACEI's, non-steroidalanti-inflammatory drugs, heparin, or trimethoprim. Also, use of thepolymeric compositions described herein will enable certain patientpopulations, who were unable to use hyperkalemia causing drugs, to usesuch drugs.

In certain chronic use situations, the preferred potassium bindingpolymers used are those that are capable of removing less than (about) 5mmol of potassium per day or in the range of (about) 5-(about) 10 mmolof potassium per day. In acute conditions, it is preferred that thepotassium binding polymers used are capable of removing (about)15-(about) 60 mmol of potassium per day.

In certain other embodiments, the compositions and methods describedherein are used in the treatment of hyperkalemia caused by a shift fromintracellular to extracellular space. Infection or trauma resulting incell disruption, especially rhabdomyolysis or lysis of muscle cells (amajor potassium store), and tumor lysis can result in acutehyperkalemia. More often, mild-to-moderate impairment of intracellularshifting of potassium occurs with diabetic ketoacidosis, acute acidosis,infusion of argentine or lysine chloride for the treatment of metabolicalkalosis, or infusion of hypertonic solutions such as 50% dextrose ormannitol. β-receptor blocking drugs can cause hyperkalemia by inhibitingthe effect of epinephrine.

In certain other embodiments, the compositions and methods describedherein are used in the treatment of hyperkalemia caused by excessiveintake of potassium. Excessive potassium intake alone is an uncommoncause of hyperkalemia. Most often, hyperkalemia is caused byindiscriminate potassium consumption in a patient with impairedmechanisms for the intracellular shift of potassium or renal potassiumexcretion. For example, sudden death among dialyzed patients who arenoncompliant in diet can be attributed to hyperkalemia.

In the present invention, the potassium-binding polymers and thecore-shell compositions can be co-administered with other activepharmaceutical agents. This co-administration can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.For example, for the treatment of hyperkalemia, the potassium-bindingpolymers and the core-shell compositions can be co-administered withdrugs that cause the hyperkalemia, such as potassium-sparing diuretics,angiotensin-convening enzyme inhibitors, non-steroidal anti-inflammatorydrugs, heparin, or trimethoprim. The drug being co-administered can beformulated together in the same dosage form and administeredsimultaneously. Alternatively, they can be simultaneously administered,wherein both the agents are present in separate formulations. In anotheralternative, the drugs are administered separately. In the separateadministration protocol, the drugs may be administered a few minutesapart, or a few hours apart, or a few days apart.

The term “treating” as used herein includes achieving a therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication, amelioration, or prevention of the underlying disorderbeing treated. For example, in a hyperkalemia patient, therapeuticbenefit includes eradication or amelioration of the underlyinghyperkalemia. Also, a therapeutic benefit is achieved with theeradication, amelioration, or prevention of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a potassium-binding polymer to a patientsuffering from hyperkalemia provides therapeutic benefit not only whenthe patient's serum potassium level is decreased, but also when animprovement is observed in the patient with respect to other disordersthat accompany hyperpkalemia like renal failure. For prophylacticbenefit, the potassium-binding polymers may be administered to a patientat risk of developing hyperpkalemia or to a patient reporting one ormore of the physiological symptoms of hyperpkalemia, even though adiagnosis of hyperpkalemia may not have been made.

The pharmaceutical compositions of the present invention includecompositions wherein the potassium binding polymers are present in aneffective amount, i.e., in an amount effective to achieve therapeutic orprophylactic benefit. The actual amount effective for a particularapplication will depend on the patient (e.g., age, weight, etc.), thecondition being treated, and the route of administration. Determinationof an effective amount is well within the capabilities of those skilledin the art, especially in light of the disclosure herein.

The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievegastrointestinal concentrations that have been found to be effective inanimals.

Generally, the dosages of the potassium binding polymers (or for sodiumbinding polymers) in animals will depend on the disease being, treated,the route of administration, and the physical characteristics of thepatient being treated. Dosage levels of the potassium binding polymersfor therapeutic and/or prophylactic uses can be from (about) 0.5 gm/dayto (about) 30 gm/day or (about) 0.5 gm/day to (about) 25 gm/day. It ispreferred that these polymers are administered along with meals. Thecompositions may be administered one time a day, two times a day, orthree times a day. Most preferred dose is (about) 15 gm/day or less. Apreferred dose range is (about) 5 gm/day to (about) 20 gm/day, morepreferred is (about) 5 gm/day to (about) 15 gm/day, even more preferredis (about) 10 gm/day to (about) 20 gm/day, and most preferred is (about)10 gm/day to (about) 15 gm/day. The dose may be administered with meals.

In some embodiments, the amount of potassium bound by the core-shellcompositions is greater than the amount if the core component, i.e.,potassium binding polymer is used in the absence of the shell. Hence,the dosage of the core component in some embodiments is lower when usedin combination with a shell compared to when the core is used withoutthe shell. Hence, in some embodiments of the core-shell pharmaceuticalcompositions, the amount of core component present in the core-shellpharmaceutical composition is less than the amount that is administeredto an animal in the absence of the shell component.

In preferred embodiments, the monovalent ion-binding polymers describedherein have a decreased tendency to cause side-effects such ashypernatremia and acidosis due to the release of detrimental ions. Theterm “detrimental ions” is used herein to refer to ions that are notdesired to be released into the body by the compositions describedherein during their period of use. Typically, the detrimental ions for acomposition depend on the condition being treated, the chemicalproperties, and/or binding properties of the composition. For example,the detrimental ion could be H⁺ which can cause acidosis or Na⁺ whichcan cause hypernatremia. Preferably the ratio of target monovalent ions(e.g., postassium ion or sodium ion) bound to detrimental cationsintroduced is 1: (about) 2.5 to (about) 4.

In preferred embodiments, the monovalent ion-binding polymers describedherein have a decreased tendency to cause other detrimentalside-effects, such as gastrointestinal discomfort, constipation,dyspepsia, etc.

Advantageously, the potential of off-target effects, such asinadvertently removing clinically relevant amounts of Ca and Mg can bereduced by the core-shell particles and compositions of the invention(relative to use of cation exchange binders in the absence of a shell).Notably, a number of studies have been reported in the literature thatdemonstrate calcium ion and magnesium ion removal by cation bindingresins. See, for example, Spencer, A. G. et al. Cation exchange in thegastrointestinal tract. Br Med J. 4862:603-6 (1954); see also Evans, B.M., et al. Ion-exchange resins in the treatment of anuria. Lancet.265:791-5 (1953). See also Berlyne, G. M., et al. Cation exchange resinsin hyperkalaemic renal failure. Isr J Med Sci. 3:45-52 (1967); see alsoMcChesney, E. W., Effects of long-term feeding of sulfonic ion exchangeresin on the growth and mineral metabolism of rats. Am J Physiol.177:395-400 (1954). In particular, studies evaluating hypocalcaemia(‘Tetany’) induced by treatment with polystyrene sulfonate resin havebeen reported. See Angelo-Nielsen K, et al., Resonium A-inducedhypocalcaemic tetany. Dan Med Bull. Sep; 30(5):348-9 (1983); see also NgY Y, et al., Reduction of serum calcium by sodium sulfonated polystyreneresin, J Formos Med Assoc. May; 89(5):399-402 (1990). Because thecompositions and core-shell particles of the invention are selectiveover such magnesium ions and calcium ions, the present invention canreduce the risk of hypocalcemia and hypomagnesemia.

The compositions described herein can be used as food products and/orfood additives. They can be added to foods prior to consumption or whilepackaging to decrease levels of potassium and/or sodium, and be removedprior to consumption so that the compositions and bound potassium and/orsodium are not ingested. Advantageously, in such application, aselective core/shell composition will release less counterion into thefood or beverage, and remove less Mg and Ca, then a non-selectivecomposition. Thus removal of potassium and/or sodium can be accomplishedwith the use of less material, and with reduced undesirable ‘off target’alteration of the ionic composition of the food or beverage. Thecompositions can also be used in fodder for animals to lower K⁺ levels(or Na+ levels), which lowering of K+ levels is for example desirablefor example in fodders for pigs and poultry to lower the watersecretion.

Formulations and Routes of Administration

The polymeric compositions and core-shell compositions described hereinor pharmaceutically acceptable salts thereof can be delivered to thepatient using a wide variety of routes or modes of administration. Themost preferred routes for administration are oral, intestinal, orrectal.

Generally, in some embodiments, the core-shell particles can be encasedor included in a bag or sachet (e.g., in a dialysis bag, or in a paperbag). In some embodiments, the core-shell particles can be formulated ina support media such as a microporous matrix or polymer gel. In someembodiments, the core-shell particles can be formulated as a suspensionor dispersion in a liquid media. Such suspension or dispersion can beuniform or non-uniform. In some embodiments, the core-shell particlescan be formulated as hollow fibers, as vesicles, as capsules, as tablet,or as a film.

If necessary, the polymers and core-shell compositions may beadministered in combination with other therapeutic agents. The choice oftherapeutic agents that can be co-administered with the compounds of theinvention will depend, in part, on the condition being treated.

The polymers (or pharmaceutically acceptable salts thereof) may beadministered per se or in the form of a pharmaceutical compositionwherein the active compound(s) is in admixture or mixture with one ormore pharmaceutically acceptable carriers, excipients or diluents.Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers compromising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For oral administration, the compounds can be formulated readily bycombining the active compound(s) with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds ofthe invention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions, wafers, and the like, fororal ingestion by a patient to be treated. In one embodiment, the oralformulation does not have an enteric coating. Pharmaceuticalpreparations for oral use can be obtained as a solid excipient,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients are, in particular, fillerssuch as sugars, including lactose, sucrose, mannitol, or sorbitol;cellulose preparations such as, for example, microcrystalline cellulose,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

For administration orally, the compounds may be formulated as asustained release preparation. Numerous techniques for formulatingsustained release preparations are known in the art.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for administration.

In some embodiments the polymers of the invention are provided aspharmaceutical compositions in the form of chewable tablets. In additionto the active ingredient, the following types of excipients are commonlyused: a sweetening agent to provide the necessary palatability, plus abinder where the former is inadequate in providing sufficient tablethardness; a lubricant to minimize frictional effects at the die wall andfacilitate tablet ejection; and, in some formulations a small amount ofa disintegrant is added to facilitate mastication. In general excipientlevels in currently-available chewable tablets are on the order of 3-5fold of active ingredient(s) whereas sweetening agents make up the bulkof the inactive ingredients.

The present invention provides chewable tablets that contain a polymeror polymers of the invention and one or more pharmaceutical excipientssuitable for formulation of a chewable tablet. The polymer used inchewable tablets of the invention preferably has a swelling ratio whiletransiting the oral cavity and in the esophagus of less than (about) 5,preferably less than (about) 4, more preferably less than (about) 3,more preferably less than 2.5, and most preferably less than (about) 2.The tablet comprising the polymer, combined with suitable excipients,provides acceptable organoleptic properties such as mouthfeel, taste,and tooth packing, and at the same time does not pose a risk to obstructthe esophagus after chewing and contact with saliva.

In some aspects of the invention, the polymer(s) provide mechanical andthermal properties that are usually performed by excipients, thusdecreasing the amount of such excipients required for the formulation.In some embodiments the active ingredient (e.g., polymer) constitutesover (about) 30%, more preferably over (about) 40%, even more preferablyover (about) 50%, and most preferably more than (about) 60% by weight ofthe chewable tablet, the remainder comprising suitable excipient(s). Insome embodiments the polymer comprises (about) 0.6 gm to (about) 2.0 gmof the total weight of the tablet, preferably (about) 0.8 gm to (about)1.6 gm. In some embodiments the polymer comprises more than (about) 0.8gm of the tablet, preferably more than (about) 1.2 gm of the tablet, andmost preferably more than (about) 1.6 gm of the tablet. The polymer isproduced to have appropriate strength/friability and particle size toprovide the same qualities for which excipients are often used, e.g.,proper hardness, good mouth feel, compressibility, and the like.Unswelled particle size for polymers used in chewable tablets of theinvention is less than (about) 80, 70, 60, 50, 40, 30, or 20 micronsmean diameter. In preferred embodiments, the unswelled particle size isless than (about) 80, more preferably less than (about) 60, and mostpreferably less than (about) 40 microns.

Pharmaceutical excipients useful in the chewable tablets of theinvention include a binder, such as microcrystalline cellulose,colloidal silica and combinations thereof (Prosolv 90), carbopol,providone and xanthan gum; a flavoring agent, such as sucrose, mannitol,xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such asmagnesium stearate, stearic acid, sodium stearyl fumurate and vegetablebased fatty acids; and, optionally, a disintegrant, such ascroscarmellose sodium, gellan gum, low-substituted hydroxypropyl etherof cellulose, sodium starch glycolate. Other additives may includeplasticizers, pigments, talc, and the like. Such additives and othersuitable ingredients are well-known in the art; see, e.g., Gennaro A R(ed), Remington's Pharmaceutical Sciences, 20th Edition.

In some embodiments the invention provides a pharmaceutical compositionformulated as a chewable tablet, comprising a polymer described hereinand a suitable excipient. In some embodiments the invention provides apharmaceutical composition formulated as a chewable tablet, comprising apolymer described herein, a filler, and a lubricant. In some embodimentsthe invention provides a pharmaceutical composition formulated as achewable tablet, comprising a polymer described herein, a filler, and alubricant, wherein the filler is chosen from the group consisting ofsucrose, mannitol, xylitol, maltodextrin, fructose, and sorbitol, andwherein the lubricant is a magnesium fatty acid salt, such as magnesiumstearate.

The tablet may be of any size and shape compatible with chewability andmouth disintegration, preferably of a cylindrical shape, with a diameterof (about) 10 mm to (about) 40 mm and a height of (about) 2 mm to(about) 10 mm, most preferably a diameter of (about) 22 mm and a heightof (about) 6 mm.

In one embodiment, the polymer is pre-formulated with a high Tg/highmelting point low molecular weight excipient such as mannitol, sorbose,sucrose in order to form a solid solution wherein the polymer and theexcipient are intimately mixed. Method of mixing such as extrusion,spray-drying, chill drying, lyophilization, or wet granulation areuseful. Indication of the level of mixing is given by known physicalmethods such as differential scanning calorimetry or dynamic mechanicalanalysis.

Methods of making chewable tablets containing pharmaceuticalingredients, including polymers, are known in the art. See, e.g.,European Patent Application No. EP373852A2 and U.S. Pat. No. 6,475,510,and Remington's Pharmaceutical Sciences, which are hereby incorporatedby reference in their entirety.

In some embodiments, the polymers are provided as dry powders in theform of a sachet or packet, which can be mixed with water or anotherbeverage of the patients choosing. Optionally the powder may beformulated with agents for providing improved sensory attributes, suchas viscosity, flavor, odor, color, and mouth feel, when the powder ismixed with water.

In some embodiments the polymers of the invention are provided aspharmaceutical compositions in the form of liquid formulations. In someembodiments the pharmaceutical composition contains an ion-bindingpolymer dispersed in a suitable liquid excipient. Suitable liquidexcipients are known in the art; see, e.g., Remington's PharmaceuticalSciences.

In this specification, the terms “about” and “around” are to signifythat in one embodiment, the respective exact value is designated, whilein another embodiment, the approximate value is designated. Thus, forexample, “at least about 1,000” shall, in one embodiment, be interpretedto mean “at least 1,000” and, in another embodiment, be interpreted tomean “at least approximately 1,000.”

DEFINITIONS

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R isR¹, R¹O—, R¹R²N—, N, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo, and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be substituted orunsubstituted and straight or branched chain or cyclic and includemethyl, ethyl, propyl, butyl, pentyl, hexyl and the like.

Unless otherwise indicated, the alkenyl groups described herein arepreferably lower alkenyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be substitutedor unsubstituted and straight or branched chain or cyclic and includeethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein arepreferably lower alkynyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be substitutedor unsubstituted and straight or branched chain and include ethynyl,propynyl, butynyl, pentynyl, hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are preferred aryl moieties.

The term “alkaryl” as used herein denote optionally substituted alkylgroups substituted with an aryl group. Exemplary aralkyl groups aresubstituted or unsubstituted benzyl, ethylphenyl, propylphenyl and thelike.

The term “carboxylic acid” refers to a RC(O)OH compound where R can behydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,substituted aryl.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring. Preferably, theheterocyclo or heterocyclic moieties have 5 or 6 atoms in each ring, atleast one of which is a heteroatom. The heterocyclo group preferably has1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and isbonded to the remainder of the molecule through a carbon or heteroatom.Exemplary heterocyclo groups include heteroaromatics as described below.Exemplary substituents include one or more of the following groups:hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,cyano, ketals, acetals, esters and ethers.

The term “heteroaryl” as used herein alone or as part of another groupdenote optionally substituted aromatic groups having at least oneheteroatom in at least one ring. Preferably, the heteroaryl moietieshave 5 or 6 atoms in each ring, at least one of which is a heteroatom.The heteroaryl group preferably has 1 or 2 oxygen atoms and/or 1 to 4nitrogen atoms and/or 1 or 2 sulfur atoms in the ring, and is bonded tothe remainder of the molecule through a carbon. Exemplary heteroarylsinclude furyl, thienyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl,pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl,pyrimidyl, pyridazinyl, thiazolyl, thiadiazolyl, biphenyl, naphthyl,indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzotriazolyl, imidazopyridinyl, benzothiazolyl,benzothiadiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl,benzofuryl and the like. Exemplary substituents include one or more ofthe following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy,protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy,halogen, amido, amino, cyano, ketals, acetals, esters and ethers.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The term “quaternary ammonium” as used herein describe an organicnitrogen moiety in which a central nitrogen atom is covalently bonded tofour organic groups.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals,acetals, esters and ethers.

Examples

The following examples are intended to illustrate certain embodimentswithin the scope of the invention. These examples are not intended to belimiting in any respect on the subject matter defined by the claims.

Example 1 Preparation of Core-Shell Particles Having CrosslinkedPolyvinylamine Shell (2 gm/100 ml scale) (Reference ID #253)

This example illustrates the preparation of a core-shell particlecomprising a core component comprising polystyrenesulfonate and a shellcomponent comprising a crosslinked polyvinylamine, using a multiphase insitu crosslinking process with 2 gm core polymer and epichlorhydrincrosslinker in a 100 ml scale reactor.

Shell Polymer.

Polyvinylamine (Mw, 340,000; >90% hydrolyzed) was provided by BASF undertrade name, lupamin9095 (20˜22 wt % in aqueous solution). As describedherein, more than 90% of the polyvinylformamide was hydrolyzed (ordeprotected) to produce polyvinylamine, but the balance of the polymercontained formamide groups, thus, a copolymer of polyvinylamine andpolyvinylamide was used. In each example where the polymer was describedas 90% hydrolyzed, this copolymer was generally the starting material.The solution was diluted with nanopure water to 2.5 wt %. The solutionpH was adjust to pH8.5 by using 33.3 wt % NaOH before coating.

Polyvinylamine, PVAm: a linear high molecular weight and water solublepolymer

Core Polymer.

A polystyrenesulfonate material, Dowex 50WX4-200, was supplied fromAldrich. It was washed extensively in 1M HCl to convert it to theH-form. It was then washed extensively in 1M NaOH. Excess NaOH wasremoved by washing in H₂O. The resins were lyophilized and stored in adesiccator.

Crosslinking Agent.

Epichlorohydrin (ECH) was purchased from Aldrich and used as received.

Reactor.

100 ml round bottom flask.

Multiphase In-Situ Crosslinking.

To a 100 ml round bottom flask were charged 2 gm of Dowex(Na) beads(core polymer) and 6 ml of 2.5 wt % aqueous solution of Lupamin 9095(pH8.5) (shell polymer) to form a first mixture. The first mixture wasgently stirred for 10 minutes. Then a separate, second mixturecomprising 6 ml of toluene and 0.584 ml of ECH was added to the firstmixture. The combined heterogeneous multiphase reaction mixture wasstirred vigorously at 85° C. oil bath for 24 hours, and cooled to roomtemperature.

Workup.

The solvent was decanted to recover the coated beads. The beads werewashed with 10 ml of methanol for ˜10 minutes, then washed with 10 ml ofwater for 3 times. The beads were isolated by filtration, and thenfreeze-dried for 3 days.

Yield.

About 1.8 gm of core-shell particles were obtained.

Example 2 Preparation of Core-Shell Particles Having CrosslinkedPolyvinylamine Shell (100 gm/1 liter scale) (Reference ID #293)

This example illustrates the preparation of a core-shell particlecomprising a core component comprising polystyrenesulfonate and a shellcomponent comprising a crosslinked polyvinylamine, using a multiphase insitu crosslinking process with 100 gm core polymer and epichlorhydrinecrosslinker in a 1 liter scale reactor.

Shell Polymer.

A polyvinylmine solution (Mw, 45,000; >90% hydrolyzed) was provided byBASF under trade name, lupamin5095 (20˜22 wt % in aqueous solution). Thesolution was diluted with nanopure water to 2.5 wt %. The solution pHwas adjust to pH8.5 by using 33.3 wt % NaOH before coating.

Core Polymer.

The core polymer was a polystyrenesulfonate material, Dowex 50WX4-200,as described in connection with Example 1.

Crosslinking Agent.

The crosslinking agent was epichlorohydrin (ECH). The ECH was providedin a toluene solution (8.9% in v/v) by mixing 29.2 ml of ECH with 300 mlof toluene.

Reactor:

A 1 L jacketed ChemGlass reactor was fitted with a stirrer and areaction vessel. To this reactor was connected an internal temperatureprobe, a nitrogen inlet, a syringe pump, and a 100 ml Dean-Starkdistillation trap with condenser and an attached bubbler. Temperaturewas controlled by a Julabo FP40-ME circulator with Solvay SolexisH-Galden ZT180 Heat Transfer Fluid (a hydrofluoropolyether). A Maximumdifference of 20° C. was allowed between the internal and jackettemperature.

Multiphase In-Situ Crosslinking.

To the above described 1 L reactor were charged 100 gm of dry Dowex(Na)beads (core polymer) and 300 ml of 2.5 wt % lupamin5095 aqueous solution(shell polymer) as a first mixture. The first mixture was stirred by themechanical stirrer at 200 rpm and heated from room temperature to 50° C.in 0.5 hour. The temperature of the first mixture was maintained at 50°C., and then 330 ml of a second mixture comprising the 8.9% ECH intoluene solution was added dropwise to first mixture in one hour whilestirring at a stirring speed of 400 rpm, forming a multiphaseheterogeneous mixture. The reaction temperature was increased to 85° C.and maintained at this temperature for 3 hours. Subsequently, water wasremoved from the heterogenous multiphase reaction mixture by azeotropicdistillation under internal temperature of 110° C. for a period of 2hours, allowing for concurrent dehydration of the multiphase mixture andfurther crosslinking. About 110 ml of water was removed from the reactorunder this procedure. Following the crosslinking reaction, the reactionmixture was cooled to 25° C. over 2 hours.

Workup.

The resulting beads were purified and isolated as follows. Toluene wasdecanted from the cooled mixture to recover the resulting core-shellparticle. (Some core-shell particle was lost while decanting thesolvent.) Then 500 ml of methanol was added to the mixture understirring for 30 min. Stirring was stopped to allow the beads to settledown at the bottom. Again the liquid phase, methanol, was decanted. Then800 ml of water was added to the beads and mixed under stirring for 30min. Afterward, water was decanted. The water washing sequence wasperformed 3 times. The slurry comprising the beads was poured into a 600ml fritted funnel and excess water was removed under reduced pressure.The wet beads were frozen at 80° C. and freeze dried.

Yield.

About 98 gm of core-shell particle were obtained.

Example 3 Preparation of Core-Shell Particles Having CrosslinkedPolyvinylamine Shell (4 gm/100 ml scale) (Reference ID #291)

This example illustrates the preparation of a core-shell particlecomprising a core component comprising polystyrenesulfonate and a shellcomponent comprising a crosslinked polyvinylamine, using a multiphase insitu crosslinking process with 4 gm core polymer andN,N-diglycidylaniline crosslinker in a 100 ml scale reactor.

Shell Polymer.

A polyvinylmine solution (Mw, 45,000; >90% hydrolyzed) was provided byBASF under trade name, lupamin5095 (20˜22 wt % in aqueous solution). Thesolution was diluted with nanopure water to 2.5 wt %. The solution pHwas adjust to pH8.5 by using 33.3 wt % NaOH before coating.

Core Polymer.

The core polymer was a polystyrenesulfonate material, Dowex 50WX4-200,as described in connection with Example 1.

Crosslinking Agent.

N,N-diglycidylaniline (N,N-DGA) was used as received from Aldrich.

Reactor:

100 ml round bottom flask, fitted with a distillation trap.

Multiphase In-Situ Crosslinking.

To a 100 ml of round bottom flask were charged 4 gm of Dowex(Na) beads(core polymer) and 12 ml of 2.5 wt % solution of Lupamin 5095 (pH8.5)(shell polymer) to form a first mixture. The first mixture was gentlystirred for 10 minutes. Then a second mixture comprising 12 ml oftoluene and 1.32 ml of N, N′-DGA were added to the first mixture,forming a heterogeneous multiphase reaction mixture. The multiphasereaction mixture was stirred vigorously at 85° C. oil bath for 3 hours,followed by removing water by azeotropic distillation at 120° C. for 40minutes. After one-fourth of the water was removed from the reactionflask, the reaction was stopped. The multiphase reaction mixture wasallowed to cool down to room temperature.

Workup.

The resulting beads were purified and isolated as follows. The solventwas decanted. The beads were washed with 20 ml of methanol for ˜10minutes, then washed with 20 ml of water. This water wash sequence wasrepeated 3 times. The beads were isolated by filtration, and thenfreeze-dried for 3 days.

Yield.

The yield was not determined.

Example 4 Binding Performance of Core-Shell Particles Having CrosslinkedPolyvinylamine Shell

This example illustrates the binding capacity of the core-shellparticles prepared in Example 1, Example 2 and Example 3 for binding ofpotassium ion in the presence of magnesium ion, as determined by invitro assays representative of the gastrointestinal tract. Controlsamples were commercially available polystyrenesulfonate cation resin(Dowex 50W X4-200(Na) 100 um beads—without a shell component).

The assays and results are described below. The following Table 4identifies, in summary form, the samples evaluated in this Example 4,their source, their internal sample reference number, and the variousfigures reporting the results for the various samples.

TABLE 4 Assay Assay Assay Sample No. 1 No. 2 No. 3 Source Ref. No. (NI)(KSPIF) (FW) Control commercial control FIG. 1 FIG. 5 FIG. 9 (Dowex(Na))[xPVAm/ Example 1 #253 FIG. 2 FIG. 6 FIG. 10 Dowex(Na)] (FL253) [xPVAm/Example 2 #293 FIG. 3 FIG. 7 FIG. 11 Dowex(Na)] (FL293) [xPVAm/ Example3 #291 FIG. 4 FIG. 8 FIG. 12 Dowex(Na)] (FL291)

Example 4A Binding Performance as Determined Using Assay No. I

In this example, the binding characteristics of the core-shell particlesof Examples 1 through 3 were determined using the in vitro assaysubstantially the same as that designated as GI Assay No. I as describedabove. This assay was a competitive assay involving potassium ion andmagnesium ion at equal concentrations selected to be generally typicaland representative of the concentrations seen in various regions of theintestinal tract. A Dowex(Na) core without the shell polymer was used asa control.

Briefly, in this assay, core-shell particles were incubated at aconcentration of 4 mg/ml in an assay solution (50 mM KCl, 50 mM MgCl₂and a buffer, 50 mM 2-morpholinoethanesulfonic acid monohydrate) at a pHof 6.5 and a temperature of 37° C. for 48 hrs with agitation. Thecations bound to the composition were determined over time, at intervalsof 2 hours, 6 hours, 24 hours and 48 hours.

The results are shown in FIGS. 1 through 4. As referenced in thefigures, this GI Assay No. I is alternatively referred to as an NI assay(non-interferring assay) and/or as being run under NI conditions.

The binding data for this assay for the control Dowex(Na) core—alone,without a shell polymer, is shown in FIG. 1. As demonstrated therein,Dowex(Na) core, without shell polymer, bound K⁺ in an amount of about0.5 meq/gm, and bound Mg⁺⁺ in an amount of more than about 3.5 meq/gmabout under the conditions of this assay. These values weresubstantially unchanged over the duration of time from 2 hrs to 48 hrs.In this FIG. 1 (and generally re each of FIGS. 2 through 12), a negativebinding capacity for sodium (shown as a negative number for ions boundin mEq/g) represents the sodium exchanged off the polymer. This providedan internal control for total binding capacity and rate of exchange.

FIG. 2 shows the binding profile from this assay for core-shellparticles comprising crosslinked polyvinylamine shell polymer on a Dowex(Na) core polymer (e.g., referred to herein using shorthand notation[xPVAm/Dowex(Na)]) as prepared in Example 1 (Ref #253). At a duration of2 hours, a K⁺ binding of 3.3 meq/gm and a Mg²⁺ binding about 0.5 meq/gmwere observed for these core-shell particles. Relatively minor changeswere observed at a duration of 6 hours. Over a time period from morethan about six hours to the end of the study, binding of Mg²⁺ increasedgradually, and binding of K⁺ decreased. Notably, however, binding of K⁺was >2 meq/gm at a duration of 6 hours and at a duration of 24 hours. At24 hours duration Mg²⁺ binding of about 1.5 meq/gm was observed. At 48hrs, a K⁺ binding value of 1.6 meq/gm was observed. Compared withbinding value for the control [Dowex(Na)]beads (0.5 meq/gm), this datarepresents a K⁺ binding value of about 3-fold improvement at theduration of 48 hours.

FIG. 3 shows the binding profile from this assay for the core-shellparticle [xPVAm/Dowex(Na)] prepared in Example 2 (Ref #293). The profileevidences about the same (if not slightly improved) selectivity andpersistence performance as shown in FIG. 2 for the core-shell asprepared in Example 1. The data demonstrates the reproducibility and thescalability of the multiphase in-situ crosslinking method, sincesubstantially similar results were obtained using the core-shellparticle prepared in Example 1 (2 gm core polymer/100 ml reactor) and inExample 2 (100 g core polymer/1 L reactor).

FIG. 4 shows the resulting binding profile from this assay forcore-shell particles [xPVAm/Dowex(Na)] prepared in Example 3 (Ref #291)using N,N-DGA crosslinker. This core-shell particle demonstrated asubstantial extent of K⁺ binding under these assay conditions throughoutthe 48 hour measurement period. Significantly, these crosslinkedcore-shell particles with xPVAm shell polymer have a remarkablypersistent permselectivity for potassium ion binding over magnesium ionbinding under the conditions of this assay.

Example 4B Binding Performance as Determined Using Assay No. II

In this example, the binding characteristics of the core-shell particlesof Examples 1 through 3 were determined using the in vitro assaydesignated as GI Assay No. II. This assay was a competitive assayinvolving potassium ion and magnesium ion and certain additional anionstypical in the upper gastrointestinal environment. A Dowex(Na) corewithout the shell polymer was used as a control.

In this assay, core shell particles were incubated at concentration of 4mg/ml in an assay solution (50 mM KCl, 50 mM MgCl₂, 5 mM sodiumtaurocholate, 30 mM oleate, 1.5 mM citrate, and a buffer, 50 mM2-morpholinoethanesulfonic acid monohydrate) at a pH of 6.5 and atemperature of 37° C. for 48 hrs with agitation. The cations bound tothe composition were determined over time, at intervals of 2 hours, 6hours, 24 hours and 48 hours.

The results are shown in FIGS. 5 through 8. As referenced in thefigures, this GI Assay No. II is alternatively referred to a K-SPIFassay (potassium specific interfering assay) and/or as being run underK-SPIF conditions.

The binding data for this assay for the control Dowex(Na) core—without ashell polymer, is shown in FIG. 5. As demonstrated therein, theDowex(Na) core bound potassium ion in an amount of about 0.8 meq/gm, butbound almost 4 meq/gm magnesium ion under the conditions of the assay.The binding capacity of these control beads was substantially unchangedover the duration of the 48 hour study.

FIG. 6 shows the binding profile from this assay for core-shellparticles [xPVAm/Dowex(Na)] prepared in Example 1 (Ref #253). Thesecore-shell particles bound K⁺ in an amount of ˜3.0 meq/gm over the first6 hours. At 24 hours and 48 hours, the core-shell particles bound K⁺ inan amount of about ˜2.5 meq/gm (24 hrs timepoint) and in an amount ofabout slightly >2.0 meq/gm (48 hrs timepoint). The core-shell particlesbound a smaller amount of Mg++, particularly over the 2 hour, 6 hour and24 hour durations, each of which was ≦2 meq/gm under the conditions ofthis assay. At the 48 hour duration, the amount of Mg++ bound wasslightly <2.0 meq/gm under the assay conditions. These data aregenerally consistent with, if not slightly improved relative to, thecorresponding data from GI Assay No. I (See FIG. 2), demonstratingdesirable performance characteristics in a relatively more complexassay.

FIG. 7 shows the binding profile from this assay for the core-shellparticle [xPVAm/Dowex(Na)] prepared in Example 2 (Ref #293). This datashows K⁺ binding of ˜3.0 meq/gm for this core-shell particle for each ofthe 2 hour, 6 hour and 24 hour timepoints. This data also demonstratespersistent permselectivity for potassium ion over magnesium ion for wellbeyond 24 hours. For example, even at 48 hrs, the magnesium ion is boundin an amount of slightly <2.0. This data also demonstrates thereproducibility and the scalability of the multiphase in-situcrosslinking method. (Compare results of FIG. 6 based on core-shellcompositions of Example 1 (2 gm core polymer/100 ml reactor) with theresults of FIG. 7 based on core-shell compositions of Example 2 (100 gcore polymer/1 L reactor).

FIG. 8 shows the resulting binding profile from this assay forcore-shell particles [xPVAm/Dowex(Na)] prepared in Example 3 (Ref #291)using N,N-DGA crosslinker. The core-shell particle demonstrated asubstantial extent of K⁺ binding under these assay conditions throughoutthe 48 hour measurement period. Significantly, these crosslinkedcore-shell particles with xPVAm shell polymer have a remarkablypersistent permselectivity for potassium ion binding over magnesium ionbinding under the conditions of this assay.

Example 4C Binding Performance as Determined Using Assay No. III

In this example, the binding characteristics of the core-shell particlesof Examples 1 through 3 were determined using the in vitro assaydesignated as GI Assay No. III. This assay was an ex vivo assayinvolving ions present in human fecal water extracts, generallyrepresentative of the ion content and concentrations seen in the lowercolon. A Dowex(Na) core without the shell polymer was used as a control.

In this fecal water assay, core-shell particles at a concentration of 4mg/ml were incubated in a fecal water solution at a temperature of 37°C. for 48 hrs with agitation. The fecal water solution was obtained bycentrifuging human feces for 16 hours at 50,000 g at 4° C. and thenfiltering the resultant supernatant through a 0.2 um filter. The cationsbound to the composition were determined over time.

The results are shown in FIGS. 9 through 12. As referenced in thefigures, this GI Assay No. III is alternatively referred to as a FWassay (fecal water assay) and/or as being run under FW conditions.

The binding data for this assay for the control Dowex(Na) core—without ashell polymer, is shown in FIG. 9. As demonstrated therein, theDowex(Na) core bound potassium ion in an amount of between about 0.5 toabout 0.8 meq/gm, but bound both calcium ion and magnesium ion,considered collectively, in an amount of about ˜3.5 meq/gm under theconditions of the fecal water assay. The binding capacities of thesecontrol beads was substantially unchanged over the duration of thestudy.

FIG. 10 shows the binding profile from this assay for core-shellparticles [xPVAm/Dowex(Na)] prepared in Example 1 (Ref #253). Thesecore-particles [xPVAm/Dowex(Na)] bound potassium ion in an amount ofmore than about 2.0 through the 48 hour study, representing a 2.5-foldimprovement in potassium binding capacity under these conditions whencompared to core alone (FIG. 9). These core-shell particles alsoeffectively minimized binding of both calcium ion and magnesium ion,each being bound in an amount of less than 0.5 meq/gm, in each caseunder the conditions of this fecal water assay. The binding capacitiesof these core-shell particles varied only moderately over the durationof the study, exemplifying the persistent permselectivity of thecore-shell particles.

FIG. 11 shows the binding profile from this assay for the core-shellparticle [xPVAm/Dowex(Na)] prepared in Example 2 (Ref #293). Thesecore-particles [xPVAm/Dowex(Na)] bound potassium ion in an amount ofmore than about 2.0 through about 40 hours, and in a slightly loweramount at 48 hours, representing a 2-fold to 2.5-fold improvement inpotassium binding capacity under these conditions when compared to corealone (FIG. 9). These core-shell particles also effectively minimizedbinding of both calcium ion and magnesium ion, each being bound in anamount of less than 0.5 meq/gm, in each case under the conditions ofthis fecal water assay. The binding capacities of these core-shellparticles varied only moderately over the duration of the study,exemplifying the persistent permselectivity of the core-shell particles.

FIG. 12 shows the resulting binding profile from this assay forcore-shell particles [xPVAm/Dowex(Na)] prepared in Example 3 (Ref #291).The core-particles [xPVAm/Dowex(Na)] bound potassium ion in an amount ofabout 2.0, representing a greater than 2-fold improvement in potassiumbinding capacity under these conditions when compared to core alone(FIG. 9), and effectively precluded binding of both calcium ion andmagnesium ion, each being bound in a negligible, in each case under theconditions of this fecal water assay. The binding capacities of thesecore-shell particles was virtually unchanged over the duration of thestudy, demonstrating persistent permselectivity of the core-shellparticles through the 48 hour study.

Example 5 Scanning Electron Microscope (SEM) Images of Core-ShellParticles Having Crosslinked Polyvinylamine Shell

Scanning electron microscope (SEM) images were taken of the core-shellparticles [xPVAm/Dowex (Na)] prepared in Examples 1 through 3. Theseimages illustrate relatively uniform shell surfaces.

FIGS. 13A and 13B show SEM images of the core-shell particle[xPVAm/Dowex (Na)] prepared in Example 1 (Ref #253) at relatively lowmagnification (FIG. 13A) and at relatively high magnification (FIG.13B).

FIGS. 14A and 14B show SEM images of the core-shell particle[xPVAm/Dowex (Na)] prepared in Example 2 (Ref #293) at relatively lowmagnification (FIG. 14A) and at relatively high magnification (FIG.14B).

FIGS. 15A and 15B show SEM images of the core-shell particle[xPVAm/Dowex (Na)] prepared in Example 3 (Ref #291) at relatively lowmagnification (FIG. 15A) and at relatively high magnification (FIG.15B).

FIGS. 16A and 16B show SEM images of the a [Dowex (Na)] particle—withouta shell component (used as a control in the experiments of Example 4) atrelatively low magnification (FIG. 16A) and at relatively highmagnification (FIG. 16B).

Example 6 Confocal Images of Core-Shell Particles Having CrosslinkedPolyvinylamine Shell

Confocal images were taken of the core-shell particles [xPVAm/Dowex(Na)] prepared in Example 1 and Example 2. A confocal image was alsotaken of a Dowex(Na) polystyrenesulfonate cation resin bead—withoutshell polymer.

Briefly, the polymeric core-shell particles were stained with AlexaFluor488 (Molecular Probes, OR Cat# A10436), 1 mg in 200 ml buffer. They werethen washed briefly to remove unbound fluorophore. The preparedparticles were imaged using a Zeiss 510 UV/Vis Meta Confocal Microscope.

FIGS. 17A through 17C show confocal images of the core particlealone—without shell [Dowex(Na)] (FIG. 17A), and of the core-shellparticle [xPVAm/Dowex (Na)] prepared in Example 2 (Ref #293) (FIG. 17B),and of the core-shell particle [xPVAm/Dowex (Na)] prepared in Example 1(Ref #253) (FIG. 17C). Size bars of 50 um and 2 um are indicated in theFIGS. 17A through 17C.

These images demonstrate a uniform shell component comprising a shellpolymer formed as a relatively thin film (having a film thickness ofabout 2 um) over a polymeric core component (FIG. 17B and FIG. 17C)having a size of about ˜120 um.

Example 7 Example for Preparation of Core-Shell Particles by CoatingPolystyrene Sulfonate (PSS or Dowex(Na)) with Crosslinked Polyvinylamine(PVAm) in 500 gm Scale at 5 L Reactor (Coating ID: #340)

This example illustrates the preparation of core-shell particles (orbeads) comprising a core component comprising polystyrenesulfonate and ashell component comprising a crosslinked polyvinylamine, using amultiphase in situ crosslinking process with 500 grams core polymer andepichlorohydrin crosslinker in a 5 liter scale reactor.

Shell Materials.

Polyvinylamine solution (Mw, 45,000; >90% hydrolyzed) was provided byBASF under trade name lupamin5095 (20˜22 wt. % in aqueous solution). Thesolution was diluted with nanopure water to 2.5 wt. %. The solution pHwas adjusted to pH 8.5 by using 33.3 wt. % sodium hydroxide (NaOH)before coating.

Polyvinylamine, PVAm: a linear high molecular weight and water solublepolymer

Core Materials.

Dowex 50WX4-200 was supplied from Aldrich. It was washed extensively in1M HCl to convert it to the H⁺-form. It was then washed extensively in1M NaOH to convert it to the Na⁺-form. Excess NaOH was removed bywashing in H₂O. The resins were lyophilized and stored in a desiccator.

Cross Linker.

Epichlorohydrin (ECH) and other chemicals were purchased from Aldrichand used as received.

ECH in toluene solution (22.6% in v/v) was prepared by mixing 146 ml ofECH with 500 ml of toluene

Reactor:

The coating and crosslinking of Dowex(Na) with polyvinylamine wascarried out in a 5 L jacketed, modified Buchi reactor. The reactor wasfitted with an internal temperature probe, a nitrogen inlet, a syringepump, a 1000 mL Dean Stark trap with condenser and an attached bubbler,a mechanical stirrer, and a steel ball valve outlet. Temperature wascontrolled by a Julabo FP40-ME circulator with Solvay Solexis H-GaldenZT180 Heat Transfer Fluid (a hydrofluoropolyether). A maximum differenceof 20° C. was allowed between the internal and jacket temperatures.

Coating/Crosslinking Procedure.

Dry Dowex(Na) beads (500 grams) and 1500 ml of 2.5 wt. % lupamin5095aqueous solution was charged to a 5 L reactor. The mixture was stirredby a mechanical stirrer at 200 rpm for 30 minutes and 500 ml of toluenewas added. The reaction temperature was raised to 85° C. and 646 ml of22.6% ECH in toluene was added drop wise to the bead mixture over onehour with stirring at 600 rpm. The internal oil temperature wasincreased to 110° C. to remove water by azeotropic distillation over 6hours. The reaction mixture was then cooled to 25° C. over 2 hours andabout 700 ml of water was removed under this procedure.

Purification and Isolation.

Toluene was decanted from the cooled mixture and 3 L of methanol wasadded to the mixture under stirring for 30 minutes. Stirring was stoppedto allow the beads to settle and again the methanol liquid phase wasdecanted. This procedure was repeated twice. Water (3 L) was added tothe beads and mixed under stirring for 30 minutes, then the water wasdecanted followed by water washing (3×3 L). The slurry beads were pouredinto 3000 mL fritted funnel and excess water was removed under reducedpressure. The wet beads were frozen and dried.

Yield.

About 480 grams of dry coated beads were obtained.

Characterization of Coated Beads.

The core-shell particles prepared under conditions described in thisexample were tested by Assay No. I (as described above in Example 4A andreferred to as non-interfering (NI) conditions) and by Assay No. II (asdescribed above in Example 4B and referred to as potassium specificinterfering assay (K-SPIF) conditions). Graphs showing the bindingprofiles for beads prepared by the method described in this example andtested under NI and K-SPIF conditions are shown in FIGS. 18(a) and18(b), respectively. Under each set of conditions, the crosslinkedpolyvinylamine/Dowex(Na) beads showed persistent and selective potassiumion binding up to and including 72 hours.

The coated beads prepared according to this method were alsocharacterized by X-ray photoelectron spectroscopy (XPS). The XPS datagenerally indicates the composition of the core-shell particles testedand differentiates the primary, secondary, tertiary, and quaternarynitrogen atoms in the polyvinylamine shell. Sample FL337 was preparedaccording to the process above wherein the ratio of the crosslinkingagent (ECH) to the number of nitrogens in the polyvinylamine was 1:1.Sample EC64028 was prepared according to the process above, except theECH:N (in PVAm) was 4:1. The XPS data is summarized in Table 5.

TABLE 5 XPS Results for PSS Core with PVAm shell NR₄ ⁺Cl⁻ C-N C-N (R═HSample #1 #2 or alkyl) Total EC64028 % N 44 46 10 100 (ECH/PVAm: 4/1)Atomic  11 (treated with 0.2N NaOH) % 5 5 1 FL337(ECH/PVAm: 1:1) % N 4744 10 ~100^(a ) Atomic  13 (treated with 0.2N NaOH) % 6 6 1EC64028(ECH/PVAm: 4/1) % N 32 55 13 100 Atomic  11 (without treatingwith base) % 4 6 1 FL337 (ECH/PVAm: 1/1) % N 33 61 6 100 Atomic  14(without treating with base) % 5 8 1 ^(a)approximate due to roundingerrors

Example 8 Binding Profiles of Core-Shell Particles Comprising a PSS Coreand a Crosslinked PVAm Shell in a Fecal Extract Assay

Collection and Preparation of Fecal Extracts.

Fecal samples were supplied by a healthy male volunteer of Caucasiandescent. Fecal samples were collected in 1-gallon Ziploc bags andimmediately mixed and transferred into PPCO Oak Ridge centrifuge tubes(Nalgene/Nunc 3319-0050). The fecal samples (representing several days'collection) were centrifuged at 21,000 rpm for 20 hours at 4° C.(Beckman JS-25.50 rotor in Beckman-Coulter Avanti J-E centrifuge). Theresulting supernatant was pooled and filtered using a Nalgene 0.2 umdisposable filter unit. The fecal extract was frozen at −20° C. untilneeded.

Method to Determine Cation Binding of Core-Shell Beads in Fecal andColonic Extracts.

The fecal extract was thawed in a room temperature water bath andstirred on a magnetic stir plate. Penicillin G/Streptomycin (Gibco,15140-122) was added to a final concentration of 100 Units/ml ofPenicillin G and 100 ug/ml of streptomycin. Sodium azide was added to afinal concentration of 100 ug/ml. Addition of antibiotics and sodiumazide discouraged bacterial and/or fungal growth during the assay.

Core-shell particle polymer samples were added to 16×100 mm glass tubesin duplicate, with each tube receiving about 50 mg of dried, accuratelyweighed sample. While stirring, fecal extract was dispensed into thetubes to produce a final concentration of 10 mg of test sample per mL ofextract. The extract was additionally dispensed into duplicate tubescontaining no test sample. All tubes were incubated for 72 hours at 37°C., rotating on a rotisserie mixer. At 6 hours, 24 hours, 48 hours and72 hours, 25 uL of each sample were diluted into 475 uL of Milli-Qpurified water (1:20 dilution). The diluted samples were then filteredby centrifugation at 13,200 rpm through Microcon YM-3 filter units (3000MWCO) for 1 hour. Filtrates were transferred to a 1 mL 96-well plate andsubmitted for analysis of cation concentrations by ion chromatography.The Dowex beads were coated by various crosslinked polyvinylamine (PVAm)shell polymers. PVAm shell FL293 was prepared by the process describedin example 2, wherein the ECH:N ratio was 4:1; PVAm shell FL294 wasprepared by the process described in example 2 wherein an ECH:N in PVAmratio of 5:1 was used, and PVAm shell FL298 was prepared by the processdescribed in example 2 wherein an ECH:N in PVAm ratio of 3:1 was used.

Ion Chromatography Method for Measurement of Cation Concentrations inFecal and Colonic Extracts.

The cation concentrations in fecal and colonic extract samples wereanalyzed using a strong cation exchange column set (Dionex CG16 50×5 mmID and CS16 250×5 mm ID), on a Dionex ICS2000 system equipped with aDionex WPS3000 auto sampler, DS3 conductivity flow cell and CSRS-UltraII 4 mm Suppressor. The ion chromatography detection method included anisocratic elution using 30 mM of methanesulfonic acid at a flow rate of1 mL/minute, and the total run time was 30 minutes per sample.

Data Analysis.

Cation binding was calculated as (C_(start)-C_(eq))/(C_(beads)*valencyof the ion), where C_(start) is the starting concentration of cation inthe fecal or colonic extract (in millimolar), C_(eq) is theconcentration of cation remaining in the sample at equilibrium afterexposure to the test agent (in millimolar), and C_(beads) corresponds tothe concentration of the test agent in the extract (in mg/mL). Thevalencies of potassium and ammonium were considered to be 1 (i.e., 1equivalent per mole) and the valencies of calcium and magnesium wereconsidered to be 2 (i.e., 2 equivalents per mole). All samples weretested in duplicate with values reported as an average (Avg)±the squareroot of the pooled variance in C_(start) and C_(eq) (Table 6, FIG. 19).The pooled variance is calculated using the following equation

$s_{P}^{2} = \frac{{\left( {n_{1} - 1} \right)s_{1}^{2}} + {\left( {n_{2} - 1} \right)s_{2}^{2}}}{n_{1} + n_{2} - 2}$

wherein s_(p) ² is the pooled variance, s₁ ² and s₂ ² represent thevariances of the first and second samples, respectively, and n₁ and n₂represent the number of data in the first and second samples.

Results.

The presence of crosslinked polyvinylamine shells on a core of Dowex 50WX4-200 increased the amount of potassium and ammonium bound by thematerial, measured in mEq of cation bound per gram of binding material,at time points measured from 6 hours to 72 hours (Table 6, FIG. 19). Theamount of divalent cations bound (magnesium and calcium) wascorrespondingly reduced by the presence of these shells.

TABLE 6 Average Binding Capacity as mEq bound/g bead (beads tested at 10mg/ml): Error = SQRT of the pooled variance Time Potassium AmmoniumMagnesium Calcium Sample (hr) Potassium Ammonium Magnesium Calcium ErrorError Error Error Na- 6 0.98 0.14 1.74 0.97 0.132 0.049 0.216 0.093Dowex 24 0.92 0.13 1.89 1.03 0.090 0.038 0.252 0.022 50w X4- 48 1.120.21 2.01 1.04 0.058 0.018 0.165 0.067 200 core 72 1.19 0.24 1.96 1.040.140 0.033 0.220 0.044 FL293 6 2.18 0.41 0.01 0.13 0.061 0.010 0.1400.121 24 2.10 0.42 1.05 0.47 0.087 0.040 0.255 0.021 48 1.41 0.31 1.180.52 0.054 0.019 0.143 0.044 72 1.45 0.31 1.54 0.65 0.267 0.055 0.2580.113 FL294 6 2.20 0.44 0.35 0.19 0.042 0.007 0.045 0.092 24 1.67 0.330.96 0.39 0.070 0.037 0.238 0.045 48 1.50 0.34 1.35 0.57 0.034 0.0160.106 0.059 72 1.44 0.33 1.55 0.62 0.074 0.020 0.115 0.027 FL298 6 2.120.42 0.40 0.18 0.072 0.022 0.012 0.087 24 1.60 0.32 1.10 0.45 0.1270.047 0.322 0.039 48 1.26 0.25 1.40 0.54 0.086 0.032 0.220 0.071 72 1.370.31 1.76 0.69 0.025 0.015 0.071 0.033

Example 9 Binding Profiles of Core-Shell Particles (Beads) Comprising aPSS Core and a Crosslinked PVAm Shell in a Fecal Extract Assay

A number of fecal binding experiments were performed essentially asdescribed in Example 8, with two differences as follows. First, bindingwas measured at a polymer concentration of 4 mg per ml of fecal extractrather than 10 mg per ml of fecal extract. Second, time points weretaken at 2, 6, 24, and 48 hours. The results are presented in Table 7.The Dowex beads were coated by various crosslinked polyvinylamine (PVAm)shell polymers. PVAm shell FL253 was prepared by the process describedin example 1; PVAm shell FL275 was prepared by the process described inexample 1 except a 5 g scale was used, and PVAm shell FL291 was preparedby the process described in example 3.

TABLE 7 Average Binding Capacity as mEq bound/g bead (beads tested at 4mg/ml): Error = SQRT of the pooled variance Time Potassium AmmoniumMagnesium Calcium Sample (hr) Potassium Ammonium Magnesium Calcium ErrorError Error Error FL253 2 2.70 0.28 0.02 0.16 0.35 0.06 0.27 0.03 6 2.060.06 −0.30 0.07 0.12 0.05 0.35 0.08 24 2.47 0.08 0.05 0.30 0.08 0.030.04 0.07 48 1.94 0.07 0.52 0.30 0.23 0.03 0.13 0.06 FL275 2 2.03 0.19−0.05 0.03 0.62 0.08 0.48 0.11 6 1.18 −0.18 −0.45 0.00 0.24 0.08 0.410.07 24 1.79 −0.06 0.28 0.25 0.09 0.03 0.17 0.08 48 1.27 −0.01 0.76 0.200.51 0.09 0.44 0.18 FL291 2 2.86 0.30 0.19 0.11 0.35 0.06 0.20 0.01 61.96 −0.10 −0.68 0.02 0.13 0.02 0.02 0.04 24 1.97 −0.07 −0.47 0.10 0.090.04 0.14 0.07 48 1.78 0.00 0.13 0.14 0.23 0.03 0.19 0.05 FL293 2 2.860.22 −0.49 −0.09 0.38 0.06 0.19 0.01 6 2.22 −0.03 −0.74 0.00 0.16 0.020.03 0.02 24 2.77 −0.02 −0.13 0.24 0.48 0.04 0.36 0.11 48 1.64 −0.070.50 0.27 0.36 0.05 0.31 0.07

Example 10 Binding Profiles of Beads Comprising a PSS Core and aCrosslinked PVAm Shell in a Colonic Extract Assay

A binding experiment was performed essentially as described in Example8, with one difference. Instead of a fecal sample, the sample used wascolonic fluid provided by a female volunteer who had recently undergonea colostomy that removed part of her terminal colon, through use of acolostomy bag. The results of this study are presented in Table 8. PVAmshells FL293, FL294, and FL298 are described above in example 8.

TABLE 8 Average Binding Capacity as mEq bound/g bead (beads tested at 10mg/ml): Error = SQRT of the pooled variance Time Potassium AmmoniumMagnesium Calcium Sample (hr) Potassium Ammonium Magnesium Calcium ErrorError Error Error Na- 6 1.54 0.42 0.89 1.07 0.120 0.026 0.092 0.147Dowex 24 1.39 0.33 0.92 1.11 0.156 0.053 0.167 0.247 50w X4- 48 1.410.34 0.95 1.14 0.072 0.034 0.179 0.210 200 core 72 1.65 0.38 0.97 1.160.058 0.005 0.079 0.168 FL293 6 2.32 0.58 0.15 0.25 0.047 0.014 0.0550.094 24 2.00 0.50 0.40 0.60 0.127 0.055 0.180 0.240 48 1.62 0.41 0.520.75 0.130 0.047 0.183 0.216 72 1.51 0.39 0.64 0.84 0.120 0.040 0.0900.169 FL294 6 2.24 0.55 0.25 0.32 0.042 0.007 0.025 0.095 24 1.55 0.410.43 0.58 0.162 0.049 0.174 0.241 48 1.89 0.48 0.69 0.84 0.096 0.0410.180 0.210 72 1.77 0.47 0.74 0.90 0.133 0.029 0.125 0.169 FL298 6 2.160.59 0.30 0.35 0.272 0.045 0.118 0.134 24 1.99 0.45 0.57 0.67 0.1190.046 0.168 0.257 48 1.50 0.40 0.66 0.80 0.078 0.031 0.187 0.227 72 2.060.52 0.81 0.89 0.379 0.053 0.154 0.177

Example 11 The Effect of Core-Shell Particles (Comprising Cross-LinkedPolyvinylamine Shell on a Polystyrene Sulfonate Core) on CationExcretion in Swine

Test Articles.

Sodium-form polystyrene sulfonate (Kayexalate; Newton Pharmacy, Canada)and Y5017N6 (a blend of crosslinked polyvinyl amine-coated sodium-formpolystyrene sulfonate beads (Dowex 50WX4-200); bead batches FL332, FL336and FL327). Batches FL332 and FL335 were prepared by the processdescribed in example 7 and FL327 was prepared by a similar process (asin example 7) except the crosslinking agent (ECH) was added at atemperature of 50° C.

Study Design.

The overall study design is shown in FIG. 20. Eighteen pigs were placedin metabolic crates, which allow separation and collection of totalfecal and urine output. They were acclimated for a period of seven dayson normal swine grower chow, with additional sodium added to account forthe sodium present as the counterion in Y5017N6. Seven animals were thencontinued on the sodium-adjusted grower chow, while four animals wereswitched to normal grower chow supplemented with Y5017N6 to give a dailydose of 1 g/kg/d and another seven animals were switched to normalgrower chow supplemented with Kayexalate (sodium-form polystyrenesulfonate) to give a daily dose of 1 g/kg/d. A bolus of ferric oxide wasgiven along with the first meal on day D(1) and on day D(9) as anindicator of transit time. Urine and feces were collected and pooled byday beginning on day D(1) and running through the end of the study. Thecation content of urine and feces was measured on days D(3) through D(8)and the effect of Y5017N6 treatment versus the control group on urineand fecal cation excretion was determined.

Animal Assignments.

Eighteen approximately 9-week old intact grower barrow swine (Camborough15 or 22 dams×Terminal Sire boars; PIC Canada Inc.) weighingapproximately 25 kg were used in this study Animals that had obvioushealth problems (e.g. weak, lame, hernia, diarrhea) or ridglings wereexcluded from the study. Seven pigs were randomly allocated to thecontrol and Kayexalate treatments. Four pigs were randomly assigned tothe Y5017N6 treatment. The pigs were housed in metabolic crates for theduration of the study, which allowed separation and collection of allurine and feces excreted by the animals. Three dietary treatments (onecontrol diet, and two test diets) were offered during one treatmentperiod in this study. During the treatment period, the treatment groupswere fed a grower diet supplemented with 1 gram of Kayexalate or ofY5017N6 per kilogram of body weight. The control group was fed astandard grower diet supplemented with the appropriate amount of sodiumbicarbonate to supply the same amount of sodium per kg diet as thatprovided by the Kayexalate and Y5017N6.

Acclimation Period.

Prior to the acclimation period, the pigs were fed a standard productiondiet. At the start of acclimation period, the 18 pigs were weighed,selected and ranked by weight. During the acclimation period, pigs weretrained to consume all food offered. Three days before the Test DietPeriod, the amounts actually fed to each pig were adjusted according totheir body weight at the beginning of the acclimation period, so thatgiven the fixed inclusion rate each pig on each treatment diet received1 g Kayexalate or Y5017N6/kg body weight/day. The amount fed to the pigson the control diet was adjusted in the same manner. This amount of feedthen remained constant for each pig for the remainder of the study.Throughout the entire study, daily feed allowances for individual pigswere divided in two equal sizes and offered at approximately 08:30 and15:30.

Test Diet Period.

After acclimation, the eleven test pigs were switched to a dietcontaining one gram of Kayexalate or Y5017N6 per kilogram of bodyweight. The seven control pigs remained on the control (acclimation)diet. These diets were for ten days.

Collection Period.

Feces and urine was collected and pooled by animal and by day. A plasticbag held in place around the anus of the pig by rings attached to theskin collected the feces. Each bag of fecal sample was individuallyweighed prior to being frozen at approximately −20° C. Feces wascollected continuously until the end of the treatment period. For eachindividual pig, the appearance of the first red feces due to the secondferric oxide bolus terminated fecal collection. The urine was collectedvia a collection tray located underneath the metabolic crate of eachpig. A funnel attached under each tray drained into plastic bottlescontaining approximately 20 mL of HCl. Urine was collected continuouslyuntil the offering of the second ferric oxide bolus. The weight of urinecollected was recorded twice each day of the collection period. Eachdaily (24 hr) fecal and urine sample for each pig was kept separate fromthe rest of the samples for that pig.

Once the Collection Period was complete, the individual frozen fecalspecimens were thawed, thoroughly mixed (i.e. each 24-hour sample wasmixed, but kept separate from the other 24-hour samples) andfreeze-dried. The freeze-dried fecal samples were ground through a 1 mmscreen to reach homogeneity for analysis.

Analysis of Cation Content in Urine and Feces.

Lyophilised fecal samples were extracted for 48 hrs in 1M HCl. Thesamples were clarified by centrifugations and the supernatant wasanalysed by flame spectroscopy for cation content. Urine samples werethawed, thoroughly mixed, and diluted 1/30 into 50 mM HCl. The diluted,mixed samples were filtered and analysed for cation content by ionchromatography. The effect of Test Articles on cation excretion wascalculated by comparing average cations excreted in the control groupwith cations excreted in the test groups during days D(3) through D(8)for feces and D(1) through D(8) for urine. The fecal analysis periodencompassed the days after the last appearance of the first ferric oxidebolus in the feces and before treatment ceased at the end of thetreatment period.

Results.

Dosing of about 1 g/kg/d Kayexalate resulted in an increased fecalexcretion of sodium, potassium, magnesium and calcium into the feces ofswine, and a reduction in the excretion of these cations into the urineof swine (FIG. 21(a) and FIG. 21(b)). Y5017N6 also resulted in anincreased average sodium and potassium secretion into the feces, and adecreased average sodium, potassium and magnesium excretion in theurine, compared to control feces and urine.

When compared to the Kayexalate-treated group, the Y5017N6 group showedincreased sodium secretion in the feces and lower divalent cationexcretion. This alteration in fecal excretion was compensated by theexpected inverse effect on urinary excretion (i.e. decreased sodiumexcretion and increased divalent cation excretion). The Y5017N6 treatedgroup showed decreased potassium excretion in the urine compared toKayexalate, but this was not mirrored by increased potassium excretionin the feces.

Example 12 Effect of Core-Shell Particles (Comprising Cross-LinkedPolyvinylamine Shell) on Cation Excretion in Rats

Test Articles.

Sodium-form polystyrene sulfonate beads (Dowex 50WX4-200; Sigma-Aldrich,Inc, St. Louis, Mo.) and sodium-form, crosslinked polyvinyl amine-coatedpolystyrene sulfonate beads from batch FL293 (prepared by the processdescribed in example 2, wherein the ECH:N ratio was 4:1).

Study Design.

The overall study design is shown in FIG. 22. Forty two rats were placedon normal rodent chow (HD2018; Harlan Teklad Inc., Madison, Wis.). Afterthree days, they were switched to a low calcium diet designed to resultin a rat fecal calcium output similar to that of humans (TD04498, HarlanTeklad Inc., Madison, Wis.). After three days acclimation on this diet,the rats were weighed, randomly assigned to seven groups of six animalseach and moved to metabolic cages, which allow separation and collectionof total fecal and urine. They were acclimated for a further 24 hours.Then, on day D(1) of the study, six groups were switched to TD04498 thathad been supplemented with Test Articles as described in FIG. 22 andTable 9. One group (group 1) remained on TD04498. Urine and feces werecollected and pooled by day on day D(−1) and on days D(3), D(4), D(5)and D(6). The cation content of urine and feces was measured on daysD(3) through D(6) and the effect of Test Article treatment versus thecontrol group on urine and fecal cation excretion was determined.

Diets.

The base diet used in days D(−4) through day D(7) of this study wasTD04498. Test articles were was mixed directly into the powder form ofTD04498 at 0.5 grams per 100 g of diet (0.5%), 1 gram per 100 g of diet(1%), or at 2 grams per 100 g of diet (2%). The TestArticle-supplemented diet was fed to the rats utilizing standardmetabolic cage procedures. The actual dose of Test Article consumed onday D(3) by each group is summarized in Table 9.

TABLE 9 Study Group Summary Actual dose Group Number of Treatmentconsumed Number Animals Groups (day 3) g/kg/d 1 6 non-treatment —control 2 6 Dowex 0.5% 0.38 3 6 Dowex 1.0% 0.82 4 6 Dowex 2.0% 1.51 5 6FL293 0.5% 0.34 6 6 FL293 1.0% 0.79 7 6 FL293 2.0% 1.62

Animals.

Animals used in the study were CD® [Crl: CD® (SD)IGS BR] rats (CharlesRiver, Wilmington, Mass.), 8 weeks of age and approximately 250 g at dayD(−1) of the study. Food and water were provided ad libitum.

Methods and Measurements.

Urine electrolytes: Urine samples were diluted 30 fold in 50 mMHydrochloric Acid and then filtered (Whatman 0.45 micron PP filterplate, 1000×g for 10 minutes). The cation concentrations in these urinesamples were analyzed using a strong cation exchange column set (DionexCG16 50×5 mm ID and CS16 250×5 mm ID), on a Dionex ICS2000 systemequipped with a Dionex AS50 auto sampler, DS3 conductivity flow cell andCSRS-Ultra II 4 mm Suppressor. The ion chromatography detection methodincluded an isocratic elution using 31 mM methanesulfonic acid at a flowrate of 1 mL/minute, and the total run time was 33 minutes per sample.

Fecal electrolytes: After collection from the metabolic cages, the feceswere frozen at minus 20° C. The frozen feces were lyophilized and thedry weight was measured. The entire dried twenty-four hour fecal samplewas homogenized with a mortar and pestle and stored at room temperature.

To a 15 mL conical tube, 200 mg of homogenized feces and 10 mL of 1N HClwas added. The fecal mixture was incubated for approximately 40 hours ona rotisserie mixer at room temperature. A sample of fecal supernatantwas isolated after centrifugation (2000×g, 15 minutes) and then filtered(Whatman 0.45 micron PP filter plate, 1000×g for 10 minutes). Thefiltrate was diluted 2 fold with Milli-Q H₂O.

Filtrate cation content was measured by inductively coupled plasmaoptical emission spectrometry (ICP-OES) using a Thermo Intrepid II XSPRadial View. Samples were infused into the spray chamber using aperistaltic pump and CETAC ASX-510 autosampler. An internal standard,yttrium (10 ppm in 1M hydrochloric acid), was employed for correctingvariation in sample flow as well as plasma conditions. The emissionlines that were used for quantifying different cations are listed inTable 10:

TABLE 10 Emission lines for quantifying cations by ICP-OES WavelengthElement (Internal Standard) Calcium 184.0 nm (224.3 nm) Magnesium 285.2nm (224.3 nm) Sodium 589.5 nm (437.4 nm) Potassium 766.4 nm (437.4 nm)

Data Analysis.

Fecal electrolytes were calculated in milliequivalents per day (mEq/day)using the following equation.

${{mEq}\text{/}{day}} = {\left\lbrack \frac{\left( {{mEq}\text{/}L\mspace{14mu} {electrolyte} \times {assay}\mspace{14mu} {volume}\mspace{14mu} (L)} \right)}{\left( {g\mspace{14mu} {feces}\mspace{14mu} {in}\mspace{14mu} {assay}} \right)} \right\rbrack \times \left\lbrack \frac{{Total}\mspace{14mu} g\mspace{14mu} {feces}}{Day} \right\rbrack}$

In the above equation, mEq/L electrolyte was the reported concentrationof an electrolyte by the ICP after adjusting for dilution factor andvalence, and total g feces per day was the amount of feces collected ina 24 hour period after lyophilization.

Urinary electrolytes were calculated in mEq electrolyte excreted per day(mEq/day) using the following equation: (mEq electrolyte per L)*(24 hoururine volume). Effect of treatment was calculated by subtracting theaverage values from the control group from the values in the treatmentgroups.

Data is presented using means±standard deviation, and/or by bar chartsof average values with standard deviations represented by error bars.The mean result from each group was determined by averaging the combinedmEq/day electrolyte values from treatment day D(3) through day D(6) foreach animal and then averaging this average result for each treatmentgroup.

Statistical analysis was performed using GraphPad Prism v4.03 (GraphPadSoftware, Inc., San Diego, Calif.). Probability (p) values werecalculated using one-way ANOVA with Tukey's post test to compare groups.

Results for sodium and potassium cations in rat urine are presented inTable 11A and FIG. 23(a).

TABLE 11A Sodium Potassium Average Std. Dev Average Std. Dev Dowex 0.5%0.37 0.21 −0.04 0.16 Dowex 1.0% 1.11 0.30 0.31 0.29 Dowex 2.0% 1.33 0.33−0.08 0.24 FL293 0.5% 0.21 0.48 −0.27 0.45 FL293 1.0% 0.17 0.42 −0.470.31 FL293 2.0% 1.28 0.63 0.02 0.50Results for sodium and potassium cations in the feces are presented inTable 11B and FIG. 23(b).

TABLE 11B Sodium Potassium Average Std. Dev Average Std. Dev Dowex 0.5%0.22 0.11 0.07 0.11 Dowex 1.0% 0.23 0.08 0.07 0.08 Dowex 2.0% 0.69 0.140.17 0.06 FL293 0.5% 0.31 0.12 0.08 0.12 FL293 1.0% 0.48 0.17 0.15 0.14FL293 2.0% 0.79 0.18 0.16 0.04

Conclusions.

FL293 dosed at 1% resulted in the greatest reduction in urinarypotassium excretion of all groups. Treatment with either Dowex or FL293resulted in an increase in sodium urinary excretion, due to theincreased sodium dosed as a counter-ion in the Test Articles.

On average, FL293 dosed at 1% resulted in 112% more potassium excretionand 111% more sodium excretion in the feces per gram of polymer dosed,when compared to Dowex dosed at the same level. This represents astatistically significant difference with respect to sodium (p<0.05).

Example 13 Core-Shell Particles Having a PSS Core and a CrosslinkedBenzylated-Polyethyleneimine (Ben-PEI) Shell Prepared by MultiphaseProcess with In Situ Crosslinking

Core Polymer.

The core polymer was PSS in the form of Dowex(Na). Dowex (H) 50W×4-200was supplied from Aldrich and was converted to Dowex(Na) before it wascoated with shell polymer.

Shell Polymer.

The shell polymer was Ben-PEI with benzylation degrees from 35 to 80%,by mole. These shell polymers were synthesized and named as Ben(35)-PEI,Ben(50)-PEI, Ben(65)-PEI, and Ben(84)-PEI, to correspondingly representpolyethyleneimine polymer benzylated at about 35 mol % (Ben(35)-PEI), atabout 50 mol %, (Ben(50)-PEI), at about 65 mol % (Ben(65)-PEI), and atabout 84 mol % Ben(84)-PEI, respectively. The solubility of a vinylbenzylated PEI polymer (R=vinyl in the structure below) was also testedand it is labeled v-Ben(40)-PEI.

Generally, these shell polymers were prepared by weighing PEI-10K (27.83g, Polysciences) into a 250 mL 3-necked flask, followed by addition of23.77 g of NaHCO₃, 71.31 g of ethanol, and 0.02 g of t-butyl catechol tothe flask. The flask was set up in the hood and fitted with a refluxcondenser, a bubbler, and an overhead stirrer. The flask was heated to70° C. and either benzyl chloride or vinyl-benzyl chloride was added inthe appropriate amount over a 2 hour period. The reaction was allowed toheat at this temperature for 24 hours and then the reaction mixture wasallowed to cool for 6 hours. Methylene chloride was added to thereaction mixture with stirring and then the mixture was allowed tosettle for 12 hours. The solid sodium salts were removed by filtrationthrough coarse, fast flow rate, fluted, filter paper. The resultingsolution was centrifuged at 1000 rpm for 1 hour. The clear solution wasdecanted and added to hexanes to precipitate the functionalized polymer.The polymer was washed several times with hexanes, dried under reducedpressure at 26° C. for 24 hours, and used as is. 51.0 g of polymer wasisolated.

Crosslinking Agent.

Epichlorohydrin (ECH) was used; it and other chemicals were purchasedfrom Aldrich and used as received.

Shell Solubility Properties.

An investigation of the shell solubility was conducted to screen shellmaterials for use in a multiphase coating process with in situcrosslinking. Preferably for such process, the shell can besubstantially soluble in the water phase and substantially insoluble inthe organic phase. Shell solution pH does affect the water solubility ofthe shell polymers. The solubility data for Ben-PEI with differentbenzylation degrees is listed in Table 9.

As shown in Table 12, Ben-PEI having low degrees of benzylation wassoluble in water and insoluble in organic solvents such as toluene,hexanes, and dodecane. With increased benzylation degree, watersolubility for Ben-PEI decreased. However, water solubility for Ben-PEIcan be altered by lowering the solution pH. For example, Ben(65)-PEI issoluble in water when the shell solution pH is below 6.5. By way offurther example, Ben(80)-PEI is sparingly soluble in water independentof the pH. As described below, Ben(35)-PEI and Ben(50)-PEI were screenedto explore the multiphase coating process with in situ crosslinking.

TABLE 12 Solubility profile of benzylated PEI Ben-PEI (benzylationSolubility degree) H2O Toluene Hexane Dodecane 35 yes up to pH 9 No NoNo 45 up to pH 8.5 No No No 50 up to pH 8.0 Swollen No No 65 up to pH6.5 Swollen No No 80 Swollen Yes Swollen Swollen V-Ben(40)-PEI SwollenSwollen No No

Variations for the Multiphase Coating Process with In Situ Crosslinking.

Experiments investigating coating with crosslinking were conducted in alibrary format of 4×6 reactors, where the crosslinking agent/shellpolymer ratio and shell solution pH varied from well to well. Thecrosslinking agent/shell polymer ratio is based on the number ofequivalents of crosslinking agent per nitrogen atom in the shellpolymer. Each well contained about 300 mg of Dowex(Na) beads, which werepremixed with 2.5 wt. % aqueous Ben(35)-PEI or Ben(50)-PEI. The amountof shell was 7.5 wt. % compared to the weight of Dowex(Na) beads. Asolution of ECH in an organic solvent such as hexanes was added. Eachwell was heated to 85° C. and reacted at this temperature for 10 hours.The coated beads were washed with methanol three times and washed withwater twice. The beads were freeze-dried for screening innon-interfering MES buffer solution of 50 mM KCl and 50 mM MgCl₂.Coating quality was evaluated by determining its degree of persistentselective binding of potassium ion over magnesium ion. These results areshown in FIGS. 24(a) to 24(d).

Other coating experiments were carried out to evaluate the effect ofcoating thickness on shell binding performance. These experiments werealso performed in a library format of 4×6 reactors. The shell solutioncontained 10 wt. % of Ben(50)-PEI and the Dowex(Na) beads were premixedwith a predetermined amount of shell solution. To these mixtures, ahexanes solution of ECH was added. This coating procedure was similar tothe previous procedure described in this example. Binding results areshown in FIGS. 25(a) to 25(c).

FIG. 24(a) depicts the effect of ECH/Ben(50)-PEI ratio on the bindingperformance of the crosslinked core-shell beads. At a lowECH/Ben(50)-PEI ratio, the coated beads do not show selective potassiumion binding; they perform more like core beads having no shell polymer.With increasing ECH/Ben(50)-PEI ratio, the coated beads show selectivebinding of potassium ion over magnesium ion at duration of 2 and 24hours. The binding curves also show that the coated beads bind potassiumion persistently, which reflects a good coating quality and good shellcomposition. With further increased ECH/Ben(50)-PEI ratio, shell bindingselectivity for potassium ion over magnesium ion decreases with time. Asuitable ECH/Ben(50)-PEI ratio range of from about 3.6 to about 8.4generally provides a shell that has the desired selectivity formonovalent ions.

FIG. 24(b) and FIG. 24(c) show more binding data for Dowex(Na) coreshaving crosslinked Ben(50)-PEI shell that were prepared from shellsolutions of pH 7.0 and 7.4, respectively. These figures show thatcoating quality is sensitive to the shell solution pH. Under theseconditions, desirable Ben(50)-PEI coating quality is obtained at a shellsolution pH between 6.5 and 7.0. If the shell solution pH is too high,the interface interaction between the shell and core will be weakeneddue to the deprotonation of the shell. However, if the shell solution pHis too low, crosslinking will not be as effective due to the stronginterface interaction between the core and shell. Therefore, in thissystem, particular pH ranges provide the desired properties of coatingcoverage and acceptable degree of crosslinking.

FIG. 24(d) shows the effect of the ECH/Ben(35)-PEI ratio on the bindingperformance of the crosslinked core-shell beads. A similar range ofECH/Ben(35)-PEI ratios was observed as compared to the ECH/Ben(50)-PEIratio ranges described above. However, Ben(35)-PEI could be acceptablycoated and crosslinked at a higher pH than Ben(50)-PEI.

FIGS. 25(a) to 25(c) show the binding performance of the crosslinkedBen(50)-PEI/Dowex(Na) particles with shell coating amounts of 20 wt. %,15 wt. %, and 10 wt. %, respectively. A thicker shell with 20 wt. %shell polymer on the Dowex(Na) beads showed desirable potassium ionbinding selectivity and binding persistence up to 24 hours (FIG. 25(a)).When there is 15 wt. % shell polymer on a Dowex(Na) core, the bindingselectivity was more desirable at 2 hours with decreasing selectivityfor monovalent ions over divalent ions at 24 hours. Use of a 10 wt. %shell polymer on a Dowex(Na) core did not show selective binding ofmonovalent ions over divalent ions even at 2 hours. These results showthat the shell coating thickness is one factor for preparing acomposition that provides selective and persistent binding of monovalentions over divalent ions.

Example 14 Coating of Benzylated PEI by Solvent Coacervation

Core Polymer.

Dowex(Na): Dowex (H) 50WX4-200 was supplied from Aldrich and wasconverted to Dowex(Na) or Dowex(K) before shell coating.

Shell Polymer.

Benzylated PEI (Ben-PEI) shells having various benzylation degrees from20 to 84 were prepared and named Ben(35)-PEI, Ben(50)-PEI, Ben(65)-PEI,and Ben(84)-PEI.

Coating Ben-PEI on Dowex(K).

Many experiments were conducted using a Dowex(K) core to explore coatingmethods. Coating quality was evaluated by binding experiments in a donorsolution of 50 mM KCl and 50 mM MgCl₂ at a bead concentration of 4mg/ml.

Experiments investigating two coacervation methods were performed toproduce Ben-PEI-coated Dowex beads. The first was the controlledprecipitation of shell materials onto beads that was driven by a solventcomposition change called “solvent coacervation.” The second was thecontrolled precipitation of shell materials onto beads by pH change.

Coating Dowex(K) with Ben(84)-PEI by Solvent Coacervation.

The shell solution was prepared as follows: 5 grams of Ben(84)-PEI wasdissolved in 178 ml of methanol, then 59.3 ml of water was added. Themixture was adjusted to pH 3 by adding 6M HCl. The final polymerconcentration was 2.5 wt. %. For coating experiments, 1 gram ofDowex(Na) was mixed with 3 gm of 2.5 wt. % Ben(84)-PEI solution. Theshell and core were mixed for 5 minutes and methanol was removed byrotary evaporation. The coated beads were isolated, washed, and dried.Results of the binding measurements using these core-shell particles areshown in FIG. 26(a). Good coating quality was observed by lowermagnesium ion as compared to core only beads.

FIG. 26(b) depicts the stability of Ben(84)-PEI coated Dowex(K) beadsunder acid conditions representative of the acidic conditions in thestomach. The core-shell beads were exposed to aqueous HCl at pH 2 for 6hours, and then isolated and dried. Binding selectivity was tested forthe post-treated beads at the same conditions described above. The shellcoating was stable and magnesium ion binding was suppressed at 6 hoursand 24 hours.

Coating Dowex(K) with Benzylated PEI by Controlled Precipitation Inducedby pH Change.

5.0 grams of Ben-PEI shell having about 20% and about 40% benzylationwas dissolved in 195 grams of neutral water to get a 2.5 wt. % solution.For coating experiments, 1 gram of Dowex(Na) was mixed with 4 grams of2.5 wt. % Ben-PEI solution. An aqueous solution of NaOH (0.1 M) wasadded drop wise to the mixture of Dowex(K) beads and shell solutionuntil the shell solution became turbid. The beads were isolated, washedwith neutral water, and dried. Binding was measured in 50 mM KCl and 50mM MgCl₂. FIG. 27(a) shows the results of the binding experiments. Thiscontrolled precipitation method for 40% benzylated PEI showed bettershell quality.

Coating Dowex(K) with Ben(40)-PEI by this controlled precipitationmethod was further conducted on a scale of 0.5 grams and 10 grams.Binding data in FIG. 27(b) showed that this coating method could providecore-shell particles having acceptable properties on this larger scale.

Coating Dowex(Na) with Ben-PEI:

The coating procedure was similar to the coating of Dowex(K). Thebinding study was conducted in 50 mM KCl and 50 mM MgCl₂. Using Natloaded Dowex(Na) beads would better reflect the shell ion selective andpermeable nature because potassium could exchange through the shell tointeract with the core polymer.

FIGS. 28(a) and 28(b) show the binding data of Ben(84)-PEI coatedDowex(Na) beads having different shell thicknesses. The procedure forthe coating is similar that described in the section Coating Dowex(K)with Ben(84)-PEI by solvent coacervation above. Sample in FIG. 27(a) has10 wt. % of Ben(84)-PEI compared with core. The sample in FIG. 28(b) hasa 2 wt. % of Ben(84)-PEI compared with Dowex(Na) core. A 10 wt. %Ben(84)-PEI coating on Dowex(Na) shows relatively slow binding kineticsfor potassium ions with good binding selectivity of potassium ion overmagnesium ion. Decreasing the shell thickness to 2 wt. % Ben(84)-PEIincreased the binding kinetics (or ion permeability) for potassium ionsand a maximum binding of potassium ions was observed at a bindingduration of 48 hours.

FIG. 28(c) shows the binding data for Ben(65)-PEI coated Dowex(Na)beads. Persistent binding selectivity for potassium ions over magnesiumions was observed.

Example 15 Quaternization of Benzyl Functionalized Polyethyleneiminethat has a Benzyl Content of 84 Mole % (Bz-PEI-84) with Methyl Iodide

An array of different ionic methyl quaternized amine levels on aBen(84)-PEI shell polymer. The procedure to prepare an array of methylquaternized benzyl-polyethyleneimine was implemented in an eight wellreactor, where the amount of the reactants was varied from well to wellas indicated in Table 13. Entries in the table correspond to the weightof chemicals that were used in the reaction well. Ben-PEI corresponds tobenzyl functionalized polyethyleneimine that has a benzyl content of 84mole % of molecular weight 10K (from Polysciences) and prepared usingthe following procedure. PEI-10K (27.83 g; Polysciences) and 23.77 g ofNaHCO₃ was weighed into was weighed into a 250 mL 3 necked flask and71.31 g of ethanol was placed into the flask. The flask was then set upin the hood and fitted with a reflux condenser, a bubbler and anoverhead stirrer. The flask was heated to 70° C. Benzyl chloride (59.58mL) was added over a 2 hour period. The reaction mixture was allowed toheat at this temperature for 24 hours and then the reaction mixture wasallowed to cool for 6 hours. Methylene chloride was added to the flaskand reaction mixture was thoroughly stirred and then allowed to settlefor 12 hours. The solid sodium salts were removed by filtration throughcoarse, fast flow rate, fluted, filter paper. The resulting solution wascentrifuged at 1000 rpm for 1 hour. The clear solution was decanted andadded to hexanes to precipitate the functionalized polymer. The polymerwas washed several times with hexanes (500 mL). The polymer was driedunder reduced pressure at 26° C. for 24 hours and was used as is. 51.0 gof polymer was isolated.

Methyl iodide was used as the reactant at the appropriate concentrationof Ben-PEI. The reaction was conducted in a bulk format (i.e, all thereactants were added into the same vial), in a 14 mL vial, with anoverhead stirrer, and was temperature controlled. The reactor was heatedto 70° C., in air for 20 hours. The product polymer was isolated byadding methylene chloride to the vials. The clear solution was added tohexanes to precipitate the quaternized polymer. The polymer was driedunder reduced pressure at 26° C. for 24 hours. The polymer was thenwashed three times in a saturated sodium chloride solution to exchangethe iodide on the polymer for chloride. The polymers were then washed anadditional three times in deionized water to remove excess sodiumchloride. The samples were then dried under reduced pressure for 24hours.

The swelling ratio of a polymer was measured by placing a polymer into apreviously weighed vial. Water was added to this vial and the polymerwas allowed to soak for 6 hours. Excess water was removed and the vialwas weighed and the weight was recorded. The wet polymer in the vial wasplaced into a lyophilizer for 24 hours to dry the polymer. The weight ofthe dry polymer was obtained. The swelling value recorded was obtainedby subtracting the weight of the dry polymer from the weight of thewater swollen polymer and dividing this resulting value by the weight ofthe dry polymer. The glass transition temperature (T_(g)) was measuredusing differential scanning calorimetry (DSC). These polymer swellingratio and glass transition temperatures are presented in Table 14.

TABLE 13 Units are in grams. Col Ben-PEI(84) MeOH MeI 1 1.032 3.0960.127 2 0.702 2.106 0.260 3 0.803 2.409 0.496 4 0.687 2.060 0.593 50.528 1.585 0.587 6 0.620 1.859 0.841 7 0.947 2.840 1.519 8 0.728 2.1841.348

TABLE 14 Sample Moles of MeI Swelling g of T_(g) number to N on PEIwater/g of gel onset T_(g)(½) 1 0.100 1.491 19.390 24.080 2 0.242 1.09235.060 39.300 3 0.384 1.000 38.000 40.000 4 0.526 1.533 51.700 52.540 50.668 1.426 55.200 57.200 6 0.810 1.345 45.900 54.300 7 0.952 1.08043.000 45.030 8 1.100 1.400 43.300 42.300

Coating of Dowex with Quaternized Benzyl-Polyethyleneimine.

The shell polymer, Ben(84)-PEI, was dissolved in a methanol and watermixture (3:1). Concentrated HCl (0.22 g) was added per gram of shellpolymer. For this process, 10 wt. % of shell polymer with respect tocore was used in the experiment. The shell and core were mixed for 5minutes. Water and methanol were removed by using a rotary evaporator(bath temperature set at 60° C.). In this example, 4 wt. % of shellpolymer was placed on the core. The coated Dowex beads were used “asis.” FIG. 29 shows a binding isotherm for two Dowex samples that containshells of differing quaternization degrees. The shell is described inthe figure as EC24159-8: Sample 8 table 13, Ben(84)-PEI with highquaternization degree and EC24159-2: Sample 2 table 13 Ben(84)-PEI withlow quaternization degree. It is observed from the figure that a higherquaternization gave faster exchanging kinetics with sustainedselectivity relative to the lower quaternized material.

Example 16 Preparation of an Array of Vinyl-Benzyl FunctionalizedPolyethyleneimine (v-Ben-PEI)

The procedure to prepare an array of functionalized polyethyleneiminewas implemented in an eight well reactor, where the nature of thereactants were varied from well to well as indicated in Table 15.Entries in the table correspond to the weight of chemicals that wereused in the reaction well. PEI corresponds to polyethyleneimine ofmolecular weight 10K (from Polysciences). The reaction was conducted ina bulk format (i.e., all the reactants were added into the same vial),in a 14 mL vial, with an overhead stirrer, and was temperaturecontrolled. The reactor was heated to 70° C., in air for 20 hours. Theproduct polymer was isolated by adding methylene chloride to the vials.The NaHCO₃ was removed by passing the reactant solution through coarse,fast flow rate, fluted, filter paper. The resulting solution wascentrifuged at 1000 rpm for 1 hour. The clear solution was decanted andadded to hexanes to precipitate the functionalized polymer. The polymerwas dried under reduced pressure at 26° C. for 24 hours.

NMR analysis was achieved by dissolving the resulting polymer from areaction element as described above in a 50/50 by weight solution ofdeuterated methanol and chloroform. Results for the measured integrationpeaks of each spectral region are given. The swelling value of a polymerwas measured by placing a polymer into a preweighed vial. Water wasadded to this vial and the polymer was allowed to soak for 6 hours.Excess water was removed and the vial was weighed and the weight wasrecorded. The wet polymer in the vial was placed into a lyophilizer for24 hours to dry the polymer. The weight of the dry polymer was obtained.The swelling value recorded was obtained by subtracting the weight ofthe dry polymer from the weight of the water swollen polymer anddividing this resulting value by the weight of the dry polymer.

TABLE 15 Components used to prepare v-Ben-PEI Library: Unit: gvinyl-benzyl Col PEI EtOH NaHCO₃ chloride. 1.00 1.37 3.03 2.02 0.49 2.001.07 3.23 2.15 0.86 3.00 1.22 3.33 2.22 1.53 4.00 1.07 3.18 2.12 1.825.00 0.90 3.38 2.25 1.95 6.00 1.06 3.53 2.35 2.77 7.00 0.81 3.14 2.092.50 8.00 0.62 3.21 2.14 2.19

TABLE 16 NMR analysis and solubility/swelling results of v-Ben-PEI.Swelling: Sample Moles of g of water number BzCl to 7 4-3 3-2 per g of(Col) N on PEI Solvent ppm ppm ppm polymer 1 0.1 CDCl₃/MeOD 4 1.5 18.9 20.226 CDCl₃/MeOD 4 1 5.8 3 0.352 CDCl₃/MeOD 4 1.8 7.9 1.90 4 0.478CDCl₃/MeOD 4 0.57 1.65 1.00 5 0.61 CDCl₃/MeOD 4 1.1 1.64 0.85 6 0.74CDCl₃/MeOD 4 1.42 2.57 0.15 7 0.87 CDCl₃/MeOD 4 1.59 2.28 0.20 8 1CDCl₃/MeOD 4 1.4 1.51 0.25

Example 17 Scale Up of v-Ben-PEI Example Between Samples 3 and 4 ofExample 16 Containing a Vinyl Benzyl Content of 40 Mole %

PEI-10K (27.83 g, Polysciences) was weighed into a 250 mL 3-neckedflask, followed by addition of 23.77 g of NaHCO₃, 71.31 g of ethanol,and 0.02 g of t-butyl catechol to the flask. The flask was set up in thehood and fitted with a reflux condenser, a bubbler, and an overheadstirrer. The flask was heated to 70° C. and vinyl-benzyl chloride wasadded over a 2 hour period. The reaction was allowed to heat at thistemperature for 24 hours and then the reaction mixture was allowed tocool for 6 hours. Methylene chloride was added to the reaction mixturewith stirring and then the mixture was allowed to settle for 12 hours.The solid sodium salts were removed by filtration through coarse, fastflow rate, fluted, filter paper. The resulting solution was centrifugedat 1000 rpm for 1 hour. The clear solution was decanted and added tohexanes to precipitate the functionalized polymer. The polymer waswashed several times with hexanes. The polymer was dried under reducedpressure at 26° C. for 24 hours and was used as is. 51.0 g of polymerwas isolated.

Example 18 Coating of Core-Shell Particles Comprising Dowex Core with av-Ben-PEI Having a Vinyl Benzyl Content of 40 Mole %

The shell, v-Ben-PEI was dissolved in a methanol and water mixture(3:1). Concentrated HCl (0.22 g) was added per gram of shell. Shellpolymer (10 wt. %) with respect to core polymer was used in theexperiment. The shell and core were mixed for 5 minutes. Water andmethanol were removed by using a rotary evaporator (bath temperature setat 60° C.) and the dried beads were used as is.

Example 19 Crosslinking v-Ben-PEI Shells on Dowex Cores

Variation of epichlorohydrin crosslinker content. The shell wasstabilized on the core using a salting out process for vinyl-benzylfunctionalized polyethyleneimine (v-Ben-PEI) coated on Dowex. A batch ofDowex beads were coated (solution coating procedure described in Example18) with polyethyleneimine functionalized with 40 mol % vinyl-benzylchloride so that the shell made up 10% of the core-shell final weight,described in table 17 as EC64010A. The coated beads were placed into aneight well reactor, where the nature of the reactants were varied fromwell to well as indicated in Table 17. Entries in the table correspondto the weight of chemicals that were used in the reaction well. A liquiddispensing robot was used to add the solutions and liquid components ofthe reaction. A solution of 0.2M sodium chloride (NaCl_s) was used alongwith neat epichlorohydrin (X-EP-1). The tubes containing the coatedDowex beads plus the reactants were then placed into an eight wellparallel reactor. The reactor was flushed with nitrogen and sealed. Thereactor was heated to 80° C. for 12 hours with stirring (250 rpm). Thetubes were taken out of the reactor and placed in a library holder. Thereactant solution was removed and the resulting products were washedwith water (2×10 mL) and methanol (2×10 mL). The library was then driedovernight under reduced pressure. The samples were then screened at 10mg bead/mL of assay solution by Assay No. I (described in more detail inExample 4A). The potassium ion and magnesium ion binding capacities forthe samples are presented in Table 18. Values that are higher than thecontrol Dowex (0.70 for K) indicate that the shell survived the washingprocess and was crosslinked. When the shell performs desirably, highpotassium binding capacity is accompanied by lower magnesium binding.

TABLE 17 Components used to prepare crosslinked v-Ben-PEI Library:ec64010 Shell Molar Dowex + at Mole ratio of Well NaCl_s X-EP-1 shell10% Moles N on X-EP-1 No. (g) (g) (g) (g) X-EP-1 shell to N 1 2.10 0.0420.42 0.042 0.00045 0.00037 1.243 2 2.50 0.088 0.5 0.05 0.00095 0.000432.175 3 2.45 0.123 0.49 0.049 0.00132 0.00043 3.107 4 2.15 0.140 0.430.043 0.00151 0.00037 4.039 5 1.90 0.152 0.38 0.038 0.00164 0.000334.971 6 2.20 0.209 0.44 0.044 0.00226 0.00038 5.903 7 1.95 0.215 0.390.039 0.00232 0.00034 6.836 8 2.00 0.250 0.4 0.04 0.00270 0.00035 7.768

TABLE 18 Ion binding results Well number 1 2 3 4 5 6 7 8 EC EC EC EC ECEC EC EC Time 64010#A1 64010#A2 64010#A3 64010#A4 64010#A5 64010#A664010#B1 64010#B2 [Mg2+] mmol/g 3 2.254 2.232 1.323 0.626 0.031 −0.0340.001 0.021 6 2.321 2.282 1.620 0.879 0.170 −0.108 0.000 0.071 24  2.3932.441 1.949 1.186 0.329 −0.008 −0.031 0.161 [K+] mmol/g 3 0.455 0.4410.453 0.534 0.653 0.963 1.438 2.285 6 0.494 0.465 0.501 0.697 1.0241.389 1.844 2.648 24  0.428 0.467 0.620 1.074 1.949 2.366 2.533 2.893[Na+] mmol/g 3 −2.673 −2.598 −1.877 −1.253 −0.813 −1.045 −1.484 −2.354 6−2.786 −2.670 −2.044 −1.492 −1.178 −1.478 −1.893 −2.688 24  −3.026−2.842 −2.398 −2.086 −2.203 −2.401 −2.607 −2.876

Example 20 Scale Up of Core-Shell Particle Comprising Crosslinked-Shelland Dowex Core

The epichlorohydrin crosslinker content was 7.76 molar equivalent foreach nitrogen on v-Ben-PEI. The shell polymer was stabilized on the coreusing a salting out process for vinyl-benzyl functionalizedpolyethyleneimine (v-Ben-PEI) coated on Dowex. Into a 3-necked, 0.5 Lround bottom flask was weighed 50.4 grams of Dowex beads that are coatedwith 10 weight % of a v-Ben-PEI shell (using the coating proceduredescribed in example 3). The flask was fitted with an overhead stirrer,a condenser, a bubbler, and a temperature probe. Then, 251 grams of 0.2molar solution of NaCl in water and 31.44 g of neat epichlorohydrin wasadded to the flask. The reaction was allowed to stir at 100 RPM for 10minutes at room temperature with a nitrogen purge. The reaction was thenallowed to heat up to 85° C. and maintained at this temperature for 12hours. The reaction was allowed to cool and the supernatant liquid wasremoved. The beads are washed with water, methanol, methylene chloride,ethanol, and finally with water 3 times. The beads were dried usingreduced pressure. Weight of dry isolated core shell bead 54.3 grams.Binding data in a NI buffer is given in table 19.

TABLE 19 Binding capacities for core-shell beads. Binding Capacity(BC)(mEq/g bead): (beads tested at 10 mg/ml) Na⁺ BC K⁺ BC Mg²⁺ BC(mEq/g) at (mEq/g) at (mEq/g) at timepoint timepoint timepoint Sample(hr): (hr): (hr): Description 2 24 2 24 2 24 EC85081-1 −2.092 −2.3881.998 1.787 0.148 0.871 EC85081-2 −2.110 −2.421 1.974 1.759 0.065 0.766

Example 21 Coating of a Fluoroacrylate Based Bead with Vinyl-BenzylPolyethyleneimine

A solution of vinyl-benzyl polyethyleneimine (preparation described inexample 17) was dissolved in an aqueous methanol solution so as to givea final polymer content of 2.5 wt. %. The final composition was 6 gramv-Ben-PEI, 1.42 gram HCl, and 234 gram methanol/water (3:1 mass %).Using a Wurster coater (fluidized bed) 40 grams of fluoroacrylate basedbeads were coated with vinyl-benzyl-polyethyleneimine. Samples weretaken during the coating process and the W090805A beads contained a 20wt. % v-Ben-PEI coating; the W090805B beads contained a 30 wt. %v-Ben-PEI coating; the W090805C beads contained a 37 wt. % v-Ben-PEIcoating; and the W090805D beads contained a 40 wt. % v-Ben-PEI coating.Binding profiles from Assay No. I (NI) are presented table 20.

TABLE 20 Ion binding profiles for various v-Ben-PEI shells on a FAA coreUn- coated standard Time W090805A W090805B W090805C W090805D bead Mg²⁺mmol/g of bead 2 5.505 5.193 4.470 4.495 6.533 6 5.234 4.759 4.404 4.6696.869 K⁺ mmol/g of bead 2 1.323 1.496 1.280 1.269 0.819 6 0.979 1.0100.988 1.086 0.950 Na⁺ mmol/g of bead 2 5.336 4.838 4.591 4.675 7.219 65.396 4.979 4.686 4.706 7.121

Example 22 Alkylation of Crosslinked Polyethyleneimine Shell of aCore-Shell Particle with Methyl Iodide

The presence of permanently quaternized amines in the shell polymer of acore-shell particle was demonstrated to have a beneficial effect onmonovalent ion permeability while maintaining permselectivity overdivalent ions. Quaternization can be achieved by crosslinking (e.g., seeExample 19) or by alkylation or by a combination thereof, including forexample by a process of exhaustive alkylation (Langmuir 1996, 12,6304-6308). Methyl iodide was used to alkylate amine functionality of anepichlorhydrin-crosslinked polyethyleneimine shell of a core-shellparticle Methyl iodide is known to form quaternized structures withalkyl amines (J. Am. Chem. Soc. 1960, 82, 4651.). In this experiment,core-shell particles were prepared in the manner described for sample 5from Example 19.

The following procedure was implemented in a four well reactor that wasequipped with controlled liquid dispensing capabilities. The nature ofthe reactants were varied from well to well as indicated in Table 21.The “Dowex beads+vBzPEI” is a Dowex bead that was coated with 10 wt. %v-Ben-PEI (shell synthesis from Example 17) using the solution coatingprocess as described in Example 18. The coated beads were placed intothe reaction vials. Then, 0.2 molar sodium chloride water solution andepichlorohydrin was added to the vial. The vials were placed into thereactor. The reactor was programmed to heat to 80° C. for 12 hours.After 6 hours, the whole amount of neat methyl iodide (MeI) was added tothe reaction vial in the amounts described in Table 21. The reaction wasrun under an atmosphere of nitrogen. After the full reaction time, thereactor was allowed to cool, and the samples were taken out of the vialsand placed into labeled centrifuge tubes. The bead products were washedwith water (45 mL), methanol (45 mL), water (45 mL), 0.2 M NaCl (45 mL)(to exchange the iodide for chloride) and water (45 mL) twice. Theexcess water was decanted and the bead products were dried under reducedpressure. The beads were screened in Assay No. I (NI) “as is” after 24hours of drying. The screening results are summarized in Table 22.

TABLE 21 Library: ec10324 Shell Moles of Moles of Dowex + at 10 Moles ofX-EP-1 MeI vBzPEI wgt % NaCl_s X-EP-1 N on MeI to N on to N on Row (g)(g) (g) (g) shell (g) shell shell 1 0.770 0.077 3.850 0.308 0.000670.000 4.970 0.000 2 0.650 0.065 3.250 0.260 0.00057 0.172 4.970 2.143 30.720 0.072 3.600 0.288 0.00063 0.381 4.970 4.286 4 0.750 0.075 3.7500.300 0.00065 0.595 4.970 6.428

TABLE 22 Binding Capacity (mEq/g bead): (beads tested at 10 mg/ml) Na BCK BC Mg BC (mEq/g) at (mEq/g) at (mEq/g) at timepoint timepointtimepoint Well (hr): (hr): (hr): no. 2 24 2 24 2 24 1 −1.14 −2.00 0.421.22 0.69 0.77 2 −1.51 −2.26 1.57 2.34 −0.09 0.10 3 −1.99 −2.35 2.152.29 0.03 0.21 4 −2.11 −2.33 2.31 2.20 −0.06 0.27

The data from Table 22 is shown in FIG. 30.

Example 23 X-Ray Photoelectron Spectroscopy (XPS) Analysis

The core-shell particles identified below in Table 23 were alsocharacterized by X-ray photoelectron spectroscopy (XPS).

TABLE 23 Molar equivalents Sample preparation Sample ID of X-EP-1 addeddescription EC64005C3 4.9 Example 19; Table 17 well 5 EC85002C 7.76Example 20 EC85075 0 Example 17

XPS data generally indicates the composition of the core-shell particlestested and differentiates the primary, secondary, tertiary, andquaternary nitrogen atoms in the polyethyleneimine shell. The core-shellparticle samples were washed with 1.0 Molar sodium hydroxide (to removeany hydrochloride salt from the bead particles). The wash sequence was0.3 g with 5 mL 1.0 M NaOH, 5 mL water, and 5 mL methanol. Then thecore-shell particles were dried under reduced pressure.

Sample EC64005C3 was a Dowex bead coated with a v-Bz-PEI and crosslinkedwith epichlorohydrin prepared according to the process wherein the ratioof the crosslinking agent (epichlorohydrin, (X-EP-1)) to the number ofnitrogens in the polyethyleneimine was 1:4.9. Sample EC85002c was aDowex bead coated with a v-Bz-PEI and crosslinked with epichlorohydrinprepared according to the process where the X-EP-1:N was 7.76:1. SampleEC85075 was the v-Bz-PEI coating alone. The XPS data which is displayedin FIG. 31 is summarized in Table 24.

TABLE 24 XPS Results for PSS Core with v-Bz-PEI shell C-N #1 C-N #2 NR₄⁺ #1 NR₄ ⁺ #2 Sample (399.1-399.2eV) (400.0ev-400.2ev) (401.5eV)(402.2eV) Total EC64005C3 % N 68 24 — 8 100 At %^(b) 7 3 — 1  11EC85002C % N 82 10 — 8 100 At % 7 1 — 1  9 EC85075 % N 76 9 15 — 100VBzPEI At % 11 1 2 — ~15^(a)  

From an XPS data base, NR₄ #1 corresponds to protonated amine. Also froman XPS data base, NR₄ #2 corresponds to quaternized amines. C—N #1 andC—N #2 correspond to primary, disubstituted, and trisubstituted amines.From table 24, it can be deduced that quaternary structures are presenton the core-shell particles having a Dowex core coated with v-Bz-PEI andthen crosslinked with epichlorohydrin when compared with the startingpolyamine coating that has not been exposed to epichlorohydrin (EC85075v-Bz-PEI).

The examples demonstrate the invention, and some of its various objectsand advantages. The examples are illustrative an non-limiting. A personof ordinary skill in the art will appreciate other alternatives withinthe scope of invention, as defined the claims hereof.

1. (canceled)
 2. A method for removing potassium from a patient in needthereof comprising administering a potassium-binding particle in an oraldosage form to the patient, the potassium-binding particle comprising amicroporous or mesoporous material, the particle having an average invitro binding capacity of at least about 2.5 mmol per gram for bindingpotassium, and the patient being administered a dose from about 0.5grams per day to about 20 grams per day.
 3. The method of claim 2wherein the dose is from about 0.5 grams per day to about 15 grams perday.
 4. The method of claim 2 wherein the dose is from about 5 grams perday to about 20 grams per day.
 5. The method of claim 2 wherein the doseis from about 5 grams per day to about 15 grams per day.
 6. The methodof claim 2 wherein the dose is from about 10 grams per day to about 20grams per day.
 7. The method of claim 2 wherein the dose is from about10 grams per day to about 15 grams per day.
 8. The method of claim 2wherein the potassium-binding particle has an average in vitro bindingcapacity of at least about 3.0 mmol per gram.
 9. The method of claim 2wherein the potassium-binding particle has an average in vitro bindingcapacity of at least about 3.5 mmol per gram.
 10. A method of treatinghyperkalemia in a patient in need thereof comprising administering apotassium-binding particle in an oral dosage form to the patient, thepotassium-binding particle comprising a microporous or mesoporousmaterial, the particle having an average in vitro binding capacity of atleast about 2.5 mmol per gram for binding potassium, and the patientbeing administered a daily dose from about 0.5 grams per day to about 20grams per day.
 11. The method of claim 10 wherein the dose is from about0.5 grams per day to about 15 grams per day.
 12. The method of claim 10wherein the dose is from about 5 grams per day to about 20 grams perday.
 13. The method of claim 10 wherein the dose is from about 5 gramsper day to about 15 grams per day.
 14. The method of claim 10 whereinthe dose is from about 10 grams per day to about 20 grams per day. 15.The method of claim 10 wherein the dose is from about 10 grams per dayto about 15 grams per day.
 16. The method of claim 10 wherein thepotassium-binding particle has an average in vitro binding capacity ofat least about 3.0 mmol per gram.
 17. The method of claim 10 wherein thepotassium-binding particle has an average in vitro binding capacity ofat least about 3.5 mmol per gram.
 18. The method of claim 2 wherein thepotassium-binding particle retains at least 5% of the bound potassium.19. The method of claim 2 wherein the potassium-binding particle retainsat least 25% of the bound potassium.
 20. The method of claim 10 whereinthe potassium-binding particle retains at least 5% of the boundpotassium.
 21. The method of claim 10 wherein the potassium-bindingparticle retains at least 25% of the bound potassium.